Receptor inhibitor, pharmaceutical composition comprising same, and use thereof

ABSTRACT

The present invention discloses a receptor inhibitor of formula (I), a pharmaceutical composition comprising the same and the use thereof.

FIELD OF THE INVENTION

The present invention relates to an angiotensin II type 2 (AT₂) receptorinhibitor, a pharmaceutical composition comprising the same, and its usefor the prophylaxis or the treatment of an AT₂ receptor-mediateddisorder or a symptom associated therewith.

BACKGROUND OF THE INVENTION

There are two known subtypes of angiotensin II (A-II) receptors, namelyAT₁ and AT₂ subtypes. In rat brain, A-II receptors are mainly of AT₂subtypes. AT₂-specific inhibitors are valuable in the treatment ofvarious cerebrovascular, cognitive, and central nervous system (CNS)diseases. In addition, AT₂ receptors are found in neuronal tumor cellsand transformed human nerve cells.

AT₂ receptors have also been implicated in the differentiation andregeneration of neuronal tissue, and the maintenance of bone mass.

In some studies, AT₂ receptor antagonism is associated with thetreatment of pain, particularly inflammatory pain and neuropathic pain,two types of pain which are difficult to treat or relieve. Impairednerve conduction velocity is also associated with nerve damage and hasbeen implicated in peripheral neuropathies, Carpal Tunnel Syndrome,ulnar neuropathy, Guillain-Barre Syndrome, fascioscapulohumeral muscledystrophy and spinal disc herniation. Impaired nerve conduction velocitymay lead to diminished reflex responses and altered peripheralsensation, such as parathesia and in some cases pain. AT₂ receptorinhibitors have been shown to restore nerve conduction velocity.

Cell proliferation and angiogenesis are important biological functionsin normal tissue. However, uncontrolled cell proliferation andangiogenesis may lead to a tumor and other proliferative disorders. AT₂receptor inhibitors have been shown to have anti-proliferative activity.

Osteoporosis is a significant problem in older populations, especiallyin postmenopausal women. The current therapies for osteoporosis rely oncalcium supplementation. However, the control the bone formation andbone resorption is complex. AT₂ receptor inhibitors have been shown toincrease bone mass.

The role of the AT₂ receptors in modulating neuronal outgrowth and theassociated effects of AT₂ receptor inhibitors on reducing neuronaloutgrowth, indicates that AT₂ receptor inhibitors may be usefultherapeutics in diseases characterized by aberrant nerve regeneration.

AT₂ receptors are also found in the reproductive organs of femalemammals, including uterus and ovaries. The role of angiotensin II in theprocesses leading to ovulation has been reported.

SUMMARY OF THE INVENTION

The present invention provides a compound for use as an AT₂ receptorinhibitor, which exhibits excellent inhibitory activity on AT₂ receptorsand excellent properties such as better physicochemical properties(e.g., solubility, physical and/or chemical stability), improvedpharmacokinetic properties (e.g., improved bioavailability, properhalf-life and duration of action), and improved safety (low toxicityand/or less side effects, wide therapeutic window). More particularly,the compound of the present invention has selective inhibitory activityon AT₂ receptors, compared to AT₁ receptors.

An aspect of the present invention provides a compound or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein the compound has a structure of formula (I) or formula(T):

wherein:

the ring C atom at the position marked with the symbol is connected tothe ring C atom at the position marked with the symbol “#” or “##”through a U group;

U is selected from the group consisting of a single bond; NR¹⁰; C₁₋₃alkylene, in which 1 or 2 CH₂ moieties are optionally replaced with agroup independently selected from the group consisting of O, S, andNR¹⁰; and C₂₋₃ alkenylene, in which any one of the CH moieties forming aC═C double bond is optionally replaced with N;

X³ is CR¹⁰ or N;

r is:

wherein

-   -   1) R^(1a), R^(1b) together with X¹ to which they are attached        form a saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group, a saturated or partially unsaturated 3- to        10-membered heterocyclic group, a C₆₋₁₀ aryl or a 5- to        14-membered heteroaryl; and    -   X⁴ is a direct bond;    -   or    -   2) R^(1a) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂        moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is        optionally replaced with O or S; a saturated or partially        unsaturated C₃₋₁₀ cyclic hydrocarbyl group; a saturated or        partially unsaturated 3- to 10-membered heterocyclic group;        C₆₋₁₀ aryl; 5- to 14-membered heteroaryl; —C₁₋₆        alkylene-saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group; —C₁₋₆ alkylene-saturated or partially        unsaturated 3- to 10-membered heterocyclic group; —C₁₋₆        alkylene-C₆₋₁₀ aryl; and —C₁₋₆ alkylene-(5- to 14-membered        heteroaryl);    -   R^(1b) does not exist, or is selected from the group consisting        of H and R^(1a);    -   X¹ does not exist, or is CR¹⁰ or N;    -   or    -   R^(1b) and X¹ together form a saturated or partially unsaturated        bivalent C₃₋₁₀ cyclic hydrocarbyl group or a saturated or        partially unsaturated bivalent 3- to 10-membered heterocyclic        group;    -   X⁴ is selected from the group consisting of a direct bond;        C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,        —O—S(═O)_(y), —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(r), wherein O, S,        NR¹⁰ are connected to X¹; preferably is a direct bond, C(═O),        S(═O)_(y), —OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or        —NR¹⁰—S(═O)_(y)—;    -   provided that: when X⁴ is a direct bond, X¹ is CR¹⁰ or N;    -   or    -   3) R^(1a) and R^(1b) are each independently C₃₋₁₀ cyclic        hydrocarbyl group; 3- to 10-membered heterocyclic group, C₆₋₁₀        aryl, or 5- to 14-membered heteroaryl, and an available ring        atom on R^(1a) is connected to an available ring atom on R^(1b)        through Y group, such that R^(1a) and R^(1b) together with X¹ to        which they are attached form an optionally substituted saturated        or partially unsaturated fused ring system containing 3 or more        rings;    -   X¹ is CR¹⁰ or N;    -   X⁴ is selected from the group consisting of C(═O); S(═O)_(y); O;        S; NR¹⁰; and —OC(═O)—, —SC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— and        —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ are connected to X¹;        preferably is C(═O) or S(═O)_(y); and    -   Y is selected from the group consisting of a; NR¹⁰; C₁₋₃        alkylene, in which 1 or 2 CH₂ moieties are optionally replaced        with a group independently selected from the group consisting of        O, S, and NR¹⁰; and C₂₋₃ alkenylene, in which any one of the CH        moieties forming a C═C double bond is optionally replaced with        N;

or

wherein

-   -   X⁶ is selected from the group consisting of O; S; NR¹⁰; and        —C(═O)—NR¹⁰— and —S(═O)_(y)—NR¹⁰—, wherein C(═O) and S(═O)_(y)        are connected to R⁹;    -   R⁹ is selected from the group consisting of H, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to        10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered        heteroaryl and C₆₋₁₂ aralkyl;

R′ is:

wherein

-   -   (1) R^(2a), R^(2b) together with X² to which they are attached        form a saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group, a saturated or partially unsaturated 3- to        10-membered heterocyclic group, a C₆₋₁₀ aryl or a 5- to        14-membered heteroaryl; and    -   X⁵ is a direct bond;    -   or    -   (2) R^(2a) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂        moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is        optionally replaced with O or S; a saturated or partially        unsaturated C₃₋₁₀ cyclic hydrocarbyl group; a saturated or        partially unsaturated 3- to 10-membered heterocyclic group;        C₆₋₁₀ aryl; 5- to 14-membered heteroaryl; —C₁₋₆        alkylene-saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group; —C₁₋₆ alkylene-saturated or partially        unsaturated 3- to 10-membered heterocyclic group; —C₁₋₆        alkylene-C₆₋₁₀ aryl; and —C₁₋₆ alkylene-(5- to 14-membered        heteroaryl);    -   R^(2b) does not exist, or is selected from the group consisting        of H and R^(2a);    -   X² does not exist, or is CR¹⁰ or N;    -   or    -   R^(2b) and X² together form a saturated or partially unsaturated        bivalent C₃₋₁₀ cyclic hydrocarbyl group or a saturated or        partially unsaturated bivalent 3- to 10-membered heterocyclic        group;    -   X⁵ is selected from the group consisting of a direct bond;        C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,        —O—S(═O)_(y), —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(r), wherein O, S,        NR¹⁰ are connected to X²; preferably is a direct bond, C(═O),        S(═O)_(y), —OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or        —NR¹⁰—S(═O)_(r);    -   provided that: when X⁵ is a direct bond, X² is CR¹⁰ or N;    -   or    -   (3) R^(2a) and R^(2b) are each independently C₃₋₁₀ cyclic        hydrocarbyl group; 3- to 10-membered heterocyclic group, C₆₋₁₀        aryl, or 5- to 14-membered heteroaryl, and an available ring        atom on R^(2a) is connected to an available ring atom on R^(2b)        through Z group, such that R^(2a) and R^(2b) together with X² to        which they are attached form an optionally substituted saturated        or partially unsaturated fused ring system containing 3 or more        rings;    -   X² is CR¹⁰ or N;    -   X⁵ is selected from the group consisting of C(═O); S(═O)_(y); O;        S; NR¹⁰; and —O—C(═O)—, —S—C(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)—        and —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ are connected to X²;        preferably is C(═O) or S(═O)_(y); and    -   Z is selected from the group consisting of a single bond; NR¹⁰;        C₁₋₃ alkylene, in which 1 or 2 CH₂ moieties are optionally        replaced with a group independently selected from the group        consisting of O, S, and NR¹⁰; and C₂₋₃ alkenylene, in which any        one of the CH moieties forming a C═C double bond is optionally        replaced with N;

R³, R⁴ and R¹⁰ are each independently selected from the group consistingof H, halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-membered heterocyclic group,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹,—P(O)(OR¹¹)(OR¹²), —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₆alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene —C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹² and —O—C₁₋₆ alkylene-NR¹¹R¹²;

R¹¹ and R¹², at each occurrence, are each independently selected fromthe group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkyl-O—, C₁₋₆ alkyl-S—, C₃₋₁₀ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland C₆₋₁₂ aralkyl;

h and k are each independently 1, 2, 3, 4, 5 or 6;

the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclichydrocarbyl group, heterocyclic group, aryl, heteroaryl and aralkyl, ateach occurrence, are each optionally substituted by 1, 2, 3 or more R¹³,wherein the R¹³, at each occurrence, is independently selected from thegroup consisting of halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-memberedheterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂aralkyl, —OR¹¹, —SR¹¹, —P(O)R¹¹R¹², —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹²,—S(═O)_(y)R¹¹, —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹S(═O)_(z)OR¹², —S(═O)_(y)NR¹¹C(═O)R¹²,—S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹², —NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹²,—NR¹¹—S(═O)_(y)—R¹², —NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆alkylene-OR¹¹, —C₁₋₆ alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹², and wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryland aralkyl recited for the substituent R¹³ are optionally furthersubstituted by 1, 2, 3 or more substituents independently selected fromthe group consisting of halogen, OH, oxo, amino, cyano, nitro, C₁₋₆alkyl, halogenated C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₃₋₆ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, 5-to 14-membered heteroaryl and C₆₋₁₂ aralkyl; and wherein theheterocyclic group, aryl or heteroaryl when being a substituent isconnected to the rest of the molecule through a ring C atom, or wherepossible, through a ring N atom;

x, at each occurrence, is independently 0, 1 or 2;

y and z, at each occurrence, are each independently 1 or 2.

Those skilled in the art understands that the above expression “X¹ doesnot exist” is intended to mean that R^(1a) and R^(1b) (when present) aredirectly connected to X⁴, and the above expression “X² does not exist”is intended to mean that R^(2a) and R^(2b) (when present) are directlyconnected to X⁵.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a prophylactically or therapeutically effectiveamount of the compound of the present invention or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, and one ormore pharmaceutically acceptable carriers, and the pharmaceuticalcomposition is preferably in the form of a solid, semi-solid, liquid, orgas preparation.

Another aspect of the present invention provides use of the compound ofthe present invention or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, or the pharmaceuticalcomposition of the present invention in the manufacture of a medicamentfor use as an AT₂ receptor inhibitor.

Another aspect of the present invention provides the compound of thepresent invention or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, or the pharmaceuticalcomposition of the present invention for use as an AT₂ receptorinhibitor.

Another aspect of the present invention provides a method for theprophylaxis or the treatment of an AT₂ receptor-mediated disorder or asymptom associated therewith, comprising administering to a subject inneed thereof an effective amount of the compound of the presentinvention or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, or the pharmaceutical composition of the presentinvention.

Another aspect of the present invention provides a method for regulatinga reproductive function associated with AT₂ receptors in a femalepatient, comprising administering to a subject in need thereof aneffective amount of the compound of the present invention or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, or the pharmaceutical composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined in the context, all technical and scientificterms used herein are intended to have the same meaning as commonlyunderstood by a person skilled in the art. References to techniquesemployed herein are intended to refer to the techniques as commonlyunderstood in the art, including variations on those techniques orsubstitutions of equivalent techniques which would be apparent to aperson skilled in the art. While it is believed that the following termswill be readily understood by a person skilled in the art, the followingdefinitions are nevertheless put forth to better illustrate the presentinvention.

The terms “contain”, “include”, “comprise”, “have”, or “relate to”, aswell as other variations used herein are inclusive or open-ended, and donot exclude additional, unrecited elements or method steps.

As used herein, the term “alkylene” refers to a saturated divalenthydrocarbyl, preferably refers to a saturated divalent hydrocarbylhaving 1, 2, 3, 4, 5 or 6 carbon atoms, e.g., methylene, ethylene,propylene or butylene.

As used herein, the term “alkyl” is defined as a linear or branchedsaturated aliphatic hydrocarbon. In some embodiments, alkyl has 1-12,particularly 1-8 (“C₁₋₈ alkyl”) carbon atoms, e.g., 1-6 (“C₁₋₆ alkyl”),1-4 (“C₁₋₄ alkyl”) carbon atoms, more particularly, 1, 2, 3, 4, 5, 6, 7or 8 carbon atoms. For example, as used herein, the term “C₁₋₈ alkyl”refers to a linear or branched group having 1-8 carbon atoms (such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, or 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl), which is optionallysubstituted with one or more (e.g., 1 to 3) suitable substituents suchas halogen (in which case the group may be referred to as “halogenatedalkyl”) (e.g., CH₂F, CHF₂, CF₃, CCl₃, C₂F₅, C₂Cl₅, CH₂CF₃, CH₂Cl or—CH₂CH₂CF₃ etch. The term “C₁₋₄ alkyl” refers to a linear or branchedaliphatic hydrocarbon chain having 1-4 carbon atoms (i.e., methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

As used herein, the term “alkenyl” refers to a linear or branchedmonovalent hydrocarbyl having a double bond and 2-8 carbon atoms (“C₂₋₈alkenyl”, such as “C₂₋₆ alkenyl”). The alkenyl is e.g., vinyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl and octenyl. When thecompound of the present invention contains an alkenylene group, thecompound may exist as the pure E (entgegen) form, the pure Z (zusammen)form, or any mixture thereof.

As used herein, the term “alkynyl” refers to a monovalent hydrocarbylcontaining one or more triple bond, and preferably having 2, 3, 4, 5, 6,7 or 8 carbon atoms, e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl.

As used herein, the terms “cyclic hydrocarbylene”, “cyclic hydrocarbyl”and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene” and“cycloalkyl”) or unsaturated (i.e., having one or more double and/ortriple bonds in the ring) monocyclic or polycyclic hydrocarbon ringhaving e.g., 3-10 (suitably having 3-8, and more suitably having 3-6,such as 5-6 or 5-7) ring carbon atoms, including but not limited tocyclopropyl(ene) (ring), cyclobutyl(ene) (ring), cyclopentyl(ene)(ring), cyclohexyl(ene) (ring), cycloheptyl(ene) (ring), cyclooctyl(ene)(ring), cyclononyl(ene) (ring), cyclohexenyl(ene) (ring), and the like.

As used herein, the terms “heterocyclyl”, “heterocyclylene” and“heterocycle” refer to a saturated (i.e., heterocycloalkyl) or partiallyunsaturated (i.e., having one or more double and/or triple bonds in thering) monocyclic or bicyclic group having e.g. 3-10 (suitably having3-8, and more suitably having 3-6; or suitably having 8-10, and moresuitably having 9 or 10) ring atoms, wherein at least one ring atom is aheteroatom selected from the group consisting of N, O and S, and theremaining ring atoms are C. For example, “3- to 10-memberedheterocyclyl(ene)” of “3- to 10-membered heterocycle” refers tosaturated or partially unsaturated monocyclic or bicyclicheterocyclyl(ene) or heterocycle having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4)heteroatoms independently selected from the group consisting of N, O andS. Examples of monocyclic heterocyclylene, heterocyclyl and heterocycleinclude, but are not limited to oxiranyl(ene), aziridinyl(ene),azetidinyl(ene), oxetanyl(ene), tetrahydrofuranyl(ene), dioxolinyl(ene),pyrrolidinyl(ene), pyrrolidonyl(ene), imidazolidinyl(ene),pyrazolidinyl(ene), pyrrolinyl(ene), tetrahydropyranyl(ene),piperidinyl(ene), morpholinyl(ene), dithianyl(ene),thiomorpholinyl(ene), piperazinyl(ene) or trithianyl(ene). Otherexamples of monocyclic heterocycle and heterocyclyl include but are notlimited to: tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl (e.g.pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl,1,3-dioxolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl(such as morpholine)), thiomorpholinyl, tetrahydro-2H-pyranyl,tetrahydro-2H-thiopyranyl, 1,3-oxazinanyl (1,3-oxazinane),1,3-thiazinanyl (1,3-thiazinane), hexahydropyrimidyl, 1,3-oxathianyl(1,3-oxathiane), 1,4-oxathianyl (1,4-oxathiane), 1,3-diazepanyl(1,3-diazepane), 1,4-diazepanyl (1,4-diazepane), 1,3-oxazepanyl(1,3-oxazepane), 1,3-thiazepanyl (1,3-thiazepane). Bicyclicheterocyclylene, heterocyclyl and heterocycle include spiro ringsystems, fused (e.g., benzo-fused) systems, or bridged systems. Thebenzo-fused heterocyclylene, heterocyclyl and heterocycle refer to theabove-mentioned monocyclic heterocyclylene, heterocyclyl and heterocyclefused to benzene, for example, a benzo derivative of a saturated orpartially unsaturated monocyclic group with 3-6 (suitably with 4-6, moresuitably 5-6) ring atoms, in which 1, 2, 3 or 4 ring atoms areheteroatoms selected from N, O and S and the remaining ring atoms are C(i.e., “7- to 10-membered benzo fused heterocyclylene, heterocyclyl andheterocycle”), including, for example,

The bridged systems also include for example 8-azaspiro[4.5]decane,3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane. Heterocyclylene,heterocyclyl and heterocycle may optionally be substituted with one ormore (e.g. 1, 2, 3 or 4) suitable substituents.

As used herein, the terms “aryl(ene)” and “aromatic ring” refer to anall-carbon monocyclic or fused-ring polycyclic aromatic group having aconjugated TL electron system. For example, as used herein, the terms“C₆₋₁₀ aryl(ene)” and “C₆₋₁₀ aromatic ring” refer to an aromatic groupcontaining 6 to 10 carbon atoms, such as phenyl(ene) (benzene ring) ornaphthyl(ene) (naphthalene ring). Aryl(ene) or aromatic ring isoptionally substituted with one or more (such as 1 to 3) suitablesubstituents (e.g., halogen, —OH, —CN, —NO₂, and C₁₋₆ alkyl, etch.

As used herein, the terms “heteroaryl(ene)” and “heteroaromatic ring”refer to a monocyclic, bicyclic or tricyclic aromatic ring system having5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least oneheteroatom (such as O, N, or S), which can be same to different.Moreover, in each case, it can be benzo-fused. In particular,“heteroaryl(ene)” or “heteroaromatic ring” is selected from the groupconsisting of thienyl(ene), furyl(ene), pyrrolyl(ene), oxazolyl(ene),thiazolyl(ene), imidazolyl(ene), pyrazolyl(ene) (e.g., 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), isoxazolyl(ene),isothiazolyl(ene), oxadiazolyl(ene), triazolyl(ene), tetrazolyl(ene)(e.g. 1-tetrazolyl or 5-tetrazolyl), thiadiazolyl(ene) etc., and benzoderivatives thereof; or pyridinyl(ene), pyridazinyl(ene),pyrimidinyl(ene), pyrazinyl(ene), triazinyl(ene), etc., and benzoderivatives thereof. Other examples of “heteroaryl(ene)” or“heteroaromatic ring” also include pyrrolopyrimidinyl, pyrrolopyridyl,pyrazolopyrimidinyl, pyrazolopyridyl, imidazopyridyl, purinyl, and thelike.

As used herein, the term “aralkyl” preferably means aryl or heteroarylsubstituted alkyl, wherein aryl, heteroaryl and alkyl are as definedherein. Normally, the aryl group may have 6-14 carbon atoms, theheteroaryl group may have 5-14 ring atoms, and the alkyl group may have1-6 carbon atoms. Exemplary aralkyl group includes, but is not limitedto, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

As used herein, the term “halo” or “halogen” are defined to include F,Cl, Br, or I.

As used herein, the term “nitrogen containing heterocycle” refers to asaturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atomin the ring, which may optionally further comprise one or more (e.g.,one, two, three or four) ring members selected from the group consistingof N, O, C═O, S, S═O and S(═O)₂. The nitrogen containing heterocycle isattached to the rest of the molecule through the nitrogen atom and anyother ring atom in said nitrogen containing heterocycle. The nitrogencontaining heterocycle is optionally benzo-fused, and is preferablyattached to the rest of the molecule through the nitrogen atom in saidnitrogen containing heterocycle and any carbon atom in the fused benzenering.

The term “substituted” means that one or more (e.g., one, two, three, orfour) hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted, or (2) substituted. If acarbon of a substituent is described as being optionally substitutedwith one or more of a list of substituents, one or more of the hydrogenson the carbon (to the extent there are any) may separately and/ortogether be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more from a list of substituents, oneor more of the hydrogens on the nitrogen (to the extent there are any)may each be replaced with an independently selected optionalsubstituent.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other(s). Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

As used herein, the term “one or more” means one or more than one (e.g.,2, 3, 4, 5 or 10) as reasonable.

As used herein, unless specified, the point of attachment of asubstituent can be from any suitable position of the substituent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any of thering-forming atoms in that ring that are substitutable, including theavailable atoms in the bridge when the substitutable ring is a bridgedring.

The present invention also includes all pharmaceutically acceptableisotopically labeled compounds, which are identical to those of thepresent invention except that one or more atoms are replaced with anatom having the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number which predominates innature. Examples of isotopes suitable for inclusion in the compound ofthe present invention include, but are not limited to, isotopes ofhydrogen, such as ²H, ³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine,such as ³⁶Cl; fluorine, such as ¹⁸F; iodine, such as ¹²³I and ¹²⁵I;nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O, and ¹⁸O;phosphorus, such as ³²P; and sulfur, such as ³⁵S. Certain isotopicallylabeled compounds of the present invention, for example thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies (e.g., assays). The radioactive isotopestritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with positron-emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, can be useful in positron emission tomography (PET)studies for examining substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byprocesses analogous to those described in the accompanying Schemesand/or in the Examples and Preparations, by using an appropriateisotopically labeled reagent in place of the non-labeled reagentpreviously employed. Pharmaceutically acceptable solvates in accordancewith the invention include those wherein the solvent of crystallizationmay be isotopically substituted, e.g., D₂O, acetone-d₆, or DMSO-d₆.

The term “stereoisomer” refers to isomers with at least one asymmetriccenter. A compound having one or more (e.g., one, two, three or four)asymmetric centers can give rise to a racemic mixture, singleenantiomer, diastereomer mixture and individual diastereomer. Certainindividual molecules may exist as geometric isomers (cis/trans).Similarly, the compound of the present invention may exist as a mixtureof two or more structurally different forms in rapid equilibrium(generally referred to as tautomer). Typical examples of a tautomerinclude a keto-enol tautomer, phenol-keto tautomer, nitroso-oximetautomer, imine-enamine tautomer and the like. It is to be understoodthat all such isomers and mixtures thereof in any proportion (such as60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) areencompassed within the scope of the present invention.

The carbon-carbon bonds of the compound of the present invention may bedepicted herein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that the stereoisomer shown ispresent. When present in racemic compounds, solid and dotted wedges areused to define relative stereochemistry, rather than absolutestereochemistry. Unless stated otherwise, it is intended that thecompound of the present invention can exist as stereoisomers, whichinclude cis and trans isomers, optical isomers such as R and Senantiomers, diastereomers, geometric isomers, rotational isomers,conformational isomers, atropisomers, and mixtures thereof. The compoundof the present invention may exhibit more than one type of isomerism,and consist of mixtures thereof (such as racemates and diastereomericpairs).

The present invention includes all possible crystalline forms orpolymorphs of the compound of the present invention, either as a singlepolymorph, or as a mixture of more than one polymorphs, in any ratio.

It also should be understood that, certain compounds of the presentinvention can be used for the treatment in a free from, or whereappropriate, in a form of a pharmaceutically acceptable derivative. Inthe present invention, the pharmaceutically acceptable derivativeincludes, but is not limited to a pharmaceutically acceptable salt,ester, solvate, N-oxide, metabolite or prodrug, which can directly orindirectly provide the compound of the present invention or a metaboliteor residue thereof after being administered to a patient in needthereof. Therefore, “the compound of the present invention” mentionedherein also means to encompass various derivative forms of the compoundas mentioned above.

A pharmaceutically acceptable salt of the compound of the presentinvention includes an acid addition salt and a base addition saltthereof.

A suitable acid addition salt is formed from an acid which forms apharmaceutically acceptable salt. Specific examples include acetate,adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibernate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

A suitable base addition salt is formed from a base which forms apharmaceutically acceptable salt. Specific examples include aluminum,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).The method for preparing a pharmaceutically acceptable salt of thecompound of the present invention is known to a person skilled in theart.

As used herein, the term “ester” refers to those derived from thecompounds of the various formulae in the present application, whichinclude physiologically-hydrolyzable esters (which may be hydrolyzedunder physiological conditions to release the compounds of the presentinvention in the form of free acids or alcohols). The compound of thepresent invention itself may be an ester as well.

The compound of the present invention can exist as a solvate (preferablya hydrate), wherein the compound of the present invention contains apolar solvent, in particular water, methanol or ethanol for example, asa structural element of the crystal lattice of the compound. The amountof the polar solvent, in particular water, may exist in a stoichiometricor non-stoichiometric ratio.

As can be appreciated by a person skilled in the art, not all nitrogencontaining heterocycles can form N-oxides since the nitrogen requires anavailable lone-pair electron for oxidation to the oxide; a personskilled in the art will recognize those nitrogen containing heterocycleswhich can form N-oxides. A person skilled in the art will also recognizethat tertiary amines can form N-oxides. Synthetic methods for thepreparation of N-oxides of heterocycles and tertiary amines are wellknown to a person skilled in the art, and they include the oxidation ofheterocycles and tertiary amines with peroxy acids such as peraceticacid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkylhydroperoxides such as tert-butyl hydroperoxide, sodium perborate, anddioxiranes such as dimethyldioxirane. These methods for the preparationof N-oxides have been extensively described and reviewed in literatures,see e.g., T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G.W. H. Cheeseman and E. S. G. Werstiuk, Advances in HeterocyclicChemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds.,Academic Press.

The metabolite of the compound of the present invention, namely asubstance formed in vivo upon administration of the compound of thepresent invention, is also included within the scope of the presentinvention. Such a product may result e.g., from the oxidation,reduction, hydrolysis, amidation, de-amidation, esterification,enzymolysis, and the like, of the administered compound. Accordingly,the present invention encompasses the metabolite of the compound of thepresent invention, including a compound produced by a method comprisingcontacting the compound of the present invention with a mammal for aperiod of time sufficient to result in a metabolic product thereof.

Also within the scope of the present invention is a prodrug of thecompound of the invention, which is certain derivative of the compoundof the invention that may have little or no pharmacological activityitself, but can, when administered into or onto the body, be convertedinto the compound of the invention having the desired activity, forexample, by hydrolytic cleavage. In general, such prodrug will be afunctional derivative of the compound which is readily converted in vivointo the compound with desired therapeutic activity. Further informationon the use of the prodrug may be found in “Pro-drugs as Novel DeliverySystems”, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Theprodrug in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compound of thepresent invention with certain moieties known to those skilled in theart as “pro-moieties” as described, for example, in “Design of Prodrugs”by H. Bundgaard (Elsevier, 1985).

The present invention further encompasses the compound of the presentinvention having a protecting group. During any of the processes forpreparation of the compound of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned, thereby resulting in the chemicallyprotected form of the compound of the present invention. This may beachieved by means of conventional protecting groups, e.g., thosedescribed in T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, John Wiley & Sons, 1991, which is incorporated herein byreference. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The term “about” refers to a range within ±10%, preferably within ±5%,and more preferably within ±2% of the specified value.

Embodiments of the Invention

Compound

In an aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof as described below.

1. A compound or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein the compound has astructure of formula (I) or formula (F):

wherein:

the ring C atom at the position marked with the symbol is connected tothe ring C atom at the position marked with the symbol “#” or “##”through a U group;

U is selected from the group consisting of a single bond; NR¹⁰; C₁₋₃alkylene, in which 1 or 2 CH₂ moieties are optionally replaced with agroup independently selected from the group consisting of O, S, andNR¹⁰; and C₂₋₃ alkenylene, in which any one of the CH moieties forming aC═C double bond is optionally replaced with N;

X³ is CR¹⁰ or N;

R is:

wherein

-   -   1) R^(1a), R^(1b) together with X¹ to which they are attached        form a saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group, a saturated or partially unsaturated 3- to        10-membered heterocyclic group, a C₆₋₁₀ aryl or a 5- to        14-membered heteroaryl; and    -   X⁴ is a direct bond;    -   or    -   2) R^(1a) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂        moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is        optionally replaced with O or S; a saturated or partially        unsaturated C₃₋₁₀ cyclic hydrocarbyl group; a saturated or        partially unsaturated 3- to 10-membered heterocyclic group;        C₆₋₁₀ aryl; 5- to 14-membered heteroaryl; —C₁₋₆        alkylene-saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group; —C₁₋₆ alkylene-saturated or partially        unsaturated 3- to 10-membered heterocyclic group; —C₁₋₆        alkylene-C₆₋₁₀ aryl; and —C₁₋₆ alkylene-(5- to 14-membered        heteroaryl);    -   R^(1b) does not exist, or is selected from the group consisting        of H and R^(1a);    -   X¹ does not exist, or is CR¹⁰ or N;    -   or    -   R^(1b) and X¹ together form a saturated or partially unsaturated        bivalent C₃₋₁₀ cyclic hydrocarbyl group or a saturated or        partially unsaturated bivalent 3- to 10-membered heterocyclic        group;    -   X⁴ is selected from the group consisting of a direct bond;        C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,        —O—S(═O)_(y), —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(r), wherein O, S,        NR¹⁰ are connected to X¹; preferably is a direct bond, C(═O),        S(═O)_(y), —OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or        —NR¹⁰—S(═O)_(y)—;    -   provided that: when X⁴ is a direct bond, X¹ is CR¹⁰ or N;    -   or    -   3) R^(1a) and R^(1b) are each independently C₃₋₁₀ cyclic        hydrocarbyl group; 3- to 10-membered heterocyclic group, C₆₋₁₀        aryl, or 5- to 14-membered heteroaryl, and an available ring        atom on R^(1a) is connected to an available ring atom on R^(1b)        through Y group, such that R^(1a) and R^(1b) together with X¹ to        which they are attached form an optionally substituted saturated        or partially unsaturated fused ring system containing 3 or more        rings;    -   X¹ is CR¹⁰ or N;    -   X⁴ is selected from the group consisting of C(═O); S(═O)_(y); O;        S; NR¹⁰; and —OC(═O)—, —SC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— and        —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ are connected to X¹;        preferably is C(═O) or S(═O)_(y); and    -   Y is selected from the group consisting of a single bond; NR¹⁰;        C₁₋₃ alkylene, in which 1 or 2 CH₂ moieties are optionally        replaced with a group independently selected from the group        consisting of O, S, and NR¹⁰; and C₂₋₃ alkenylene, in which any        one of the CH moieties forming a C═C double bond is optionally        replaced with N;

or

wherein

-   -   X⁶ is selected from the group consisting of O; S; NR¹⁰; and        —C(═O)—NR¹⁰— and —S(═O)_(y)—NR¹⁰—, wherein C(═O) and S(═O)_(y)        are connected to R⁹;    -   R⁹ is selected from the group consisting of H, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to        10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered        heteroaryl and C₆₋₁₂ aralkyl;

R′ is;

wherein

-   -   (1) R^(2a), R^(2b) together with X² to which they are attached        form a saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group, a saturated or partially unsaturated 3- to        10-membered heterocyclic group, a C₆₋₁₀ aryl or a 5- to        14-membered heteroaryl; and    -   X⁵ is a direct bond;    -   or    -   (2) R^(2a) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂        moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is        optionally replaced with O or S; a saturated or partially        unsaturated C₃₋₁₀ cyclic hydrocarbyl group; a saturated or        partially unsaturated 3- to 10-membered heterocyclic group;        C₆₋₁₀ aryl; 5- to 14-membered heteroaryl; —C₁₋₆        alkylene-saturated or partially unsaturated C₃₋₁₀ cyclic        hydrocarbyl group; —C₁₋₆ alkylene-saturated or partially        unsaturated 3- to 10-membered heterocyclic group; —C₁₋₆        alkylene-C₆₋₁₀ aryl; and —C₁₋₆ alkylene-(5- to 14-membered        heteroaryl);    -   R^(2b) does not exist, or is selected from the group consisting        of H and R^(2a);    -   X² does not exist, or is CR¹⁰ or N;    -   or    -   R^(2b) and X² together form a saturated or partially unsaturated        bivalent C₃₋₁₀ cyclic hydrocarbyl group or a saturated or        partially unsaturated bivalent 3- to 10-membered heterocyclic        group;    -   X⁵ is selected from the group consisting of a direct bond;        C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,        —O—S(═O)_(r), —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein O, S,        NR¹⁰ are connected to X²; preferably is a direct bond, C(═O),        S(═O)_(y), —OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or        —NR¹⁰—S(═O)_(y)—;    -   provided that: when X⁵ is a direct bond, X² is CR¹⁰ or N;    -   or    -   (3) R^(2a) and R^(2b) are each independently C₃₋₁₀ cyclic        hydrocarbyl group; 3- to 10-membered heterocyclic group, C₆₋₁₀        aryl, or 5- to 14-membered heteroaryl, and an available ring        atom on R^(2a) is connected to an available ring atom on R^(2b)        through Z group, such that R^(2a) and R^(2b) together with X² to        which they are attached form an optionally substituted saturated        or partially unsaturated fused ring system containing 3 or more        rings;    -   X² is CR¹⁰ or N;    -   X⁵ is selected from the group consisting of C(═O); S(═O)_(y); O;        S; NR¹⁰; and —O—C(═O)—, —S—C(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)—        and —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ are connected to X²;        preferably is C(═O) or S(═O)_(y); and    -   Z is selected from the group consisting of a single bond; NR¹⁰;        C₁₋₃ alkylene, in which 1 or 2 CH₂ moieties are optionally        replaced with a group independently selected from the group        consisting of O, S, and NR¹⁰; and C₂₋₃ alkenylene, in which any        one of the CH moieties forming a C═C double bond is optionally        replaced with N;

R³, R⁴ and R¹⁰ are each independently selected from the group consistingof H, halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-membered heterocyclic group,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹,—P(O)(OR¹¹)(OR¹²), —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₆alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene —C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹² and —O—C₁₋₆ alkylene-NR¹¹R¹²;

R¹¹ and R¹², at each occurrence, are each independently selected fromthe group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkyl-O—, C₁₋₆ alkyl-S—, C₃₋₁₀ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland C₆₋₁₂ aralkyl;

h and k are each independently 1, 2, 3, 4, 5 or 6;

the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclichydrocarbyl group, heterocyclic group, aryl, heteroaryl and aralkyl, ateach occurrence, are each optionally substituted by 1, 2, 3 or more R¹³,wherein the R¹³, at each occurrence, is independently selected from thegroup consisting of halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-memberedheterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂aralkyl, —OR¹¹, —SR¹¹, —P(O)R¹¹R¹², —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹²,—S(═O)_(y)R¹¹, —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹S(═O)_(z)OR¹², —S(═O)_(y)NR¹¹C(═O)R¹²,—S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹², —NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹²,—NR¹¹—S(═O)_(y)—R¹², —NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆alkylene-OR¹¹, —C₁₋₆ alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹², and wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryland aralkyl recited for the substituent R¹³ are optionally furthersubstituted by 1, 2, 3 or more substituents independently selected fromthe group consisting of halogen, OH, oxo, amino, cyano, nitro, C₁₋₆alkyl, halogenated C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₃₋₆ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, 5-to 14-membered heteroaryl and C₆₋₁₂ aralkyl; and wherein theheterocyclic group, aryl or heteroaryl when being a substituent isconnected to the rest of the molecule through a ring C atom, or wherepossible, through a ring N atom;

x, at each occurrence, is independently 0, 1 or 2;

y and z, at each occurrence, are each independently 1 or 2.

2. The compound according to item 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of formula (I):

wherein:

R³, R⁴ and R¹⁰ are each independently selected from the group consistingof H, halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-membered heterocyclic group,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹,—OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₆alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹²; and

R¹³, at each occurrence, is independently selected from the groupconsisting of halogen, cyano, nitro, C₁₋₆ alkyl, C₃₋₁₀ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, 5-to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹, —OC(═O)R¹¹,—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹, —S(═O)_(y)OR¹¹,—S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹², —S(═O)_(y)NR¹¹C(═O)R¹²,—S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹², —NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹²,—NR¹¹—S(═O)_(y)—R¹², —NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆alkylene-OR¹¹, —C₁₋₆ alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹², and wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryland aralkyl recited for the substituent R¹³ are optionally furthersubstituted by 1, 2, 3 or more substituents independently selected fromthe group consisting of halogen, OH, oxo, amino, cyano, nitro, C₁₋₆alkyl, halogenated C₁₋₆ alkyl, C₃₋₆ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland C₆₋₁₂ aralkyl; and wherein the heterocyclic group, aryl orheteroaryl when being a substituent is connected to the rest of themolecule through a ring C atom, or where possible, through a ring Natom.

3. The compound according to item 1 or 2, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein Uis a single bond, NR¹⁰, O, S, methylene, ethylene, —CH₂—O—, —O—CH₂—,—CH₂—S—, —S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—, —CH═CH—, —CH═N— or —N═CH—;preferably, U is a single bond, methylene or ethylene.

4. The compound according to any one of items 1 to 3, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R³ is F, Cl, Br, I, amino, cyano, nitro, C₁₋₄ alkyl,C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclic heterocyclicgroup, phenyl, 5- to 7-membered heteroaryl, —OR¹¹, —SR¹¹, —OC(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₄ alkylene-OR¹¹,—C₁₋₄ alkylene-OC(═O)R¹¹, —C₁₋₄ alkylene-C(═O)OR¹¹, —C₁₋₄alkylene-S(═O)_(y)OR¹¹, —C₁₋₄ alkylene-OC(═O)NR¹¹R¹², —C₁₋₄alkylene-C(═O)NR¹¹R¹², —C₁₋₄ alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄alkylene-S(═O)_(y)NR¹¹R¹²; preferably is 5- to 6-membered heteroaryl,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₃alkylene-OC(═O)R¹¹, —C₁₋₃ alkylene-C(═O)OR¹¹, —C₁₋₃alkylene-S(═O)_(y)OR¹¹, —C₁₋₃ alkylene-C(═O)NR¹¹R¹² or —C₁₋₃alkylene-S(═O)_(y)NR¹¹R¹²; more preferably is 5- to 6-memberedheteroaryl (such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl such as 1-tetrazolyl or 5-tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl), —C(═O)OR¹¹ (such asCOOH, COOCH₃ or COOCH₂CH₃), —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹² (such as

—C(═O)NR¹¹S(═O)_(y)R¹² (such as

—C(═O)NR¹¹R¹², —S(═O)_(y)OR¹¹ or —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹² (such as

5. The compound according to any one of items 1 to 3, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R³ is —P(O)(OR¹¹)(OR¹²), preferably —P(O)(OH)₂,—P(O)(OH)(OC₁₋₆ alkyl) or —P(O)(OC₁₋₆ alkyl)₂, preferably —P(O)(OH)₂,—P(O)(OH)(OC₁₋₃ alkyl) or —P(O)(OC₁₋₃ alkyl)₂, more preferably—P(O)(OH)₂, —P(O)(OH)(OCH₃) or —P(O)(OH)(OCH₂CH₃).

6. The compound according to any one of items 1 to 5, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R⁴ and R¹⁰, at each occurrence, are each independentlyH, F, Cl, Br, I, amino, cyano, nitro, CM alkyl, C₅₋₇ cyclic hydrocarbylgroup, 5- to 7-membered monocyclic heterocyclic group, phenyl, 5- to6-membered heteroaryl, —OR¹¹, —SR¹¹, —OC(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹²,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹C(═O)R¹²,—S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₄ alkylene-OR¹¹, —C₁₋₄ alkylene-OC(═O)R¹¹,—C₁₋₄ alkylene-C(═O)OR¹¹, —C₁₋₄ alkylene-S(═O)_(y)OR¹¹, —C₁₋₄alkylene-OC(═O)NR¹¹R¹², —C₁₋₄ alkylene-C(═O)NR¹¹R¹², —C₁₋₄alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄ alkylene-S(═O)_(y)NR¹¹R¹²; preferably H,F, Cl, Br, I, OH, amino, cyano, nitro or C₁₋₄ alkyl (e.g. methyl).

7. The compound according to any one of items 1 to 6, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹¹ and R¹² at each occurrence are each independentlyselected from the group consisting of H, C₁₋₄ alkyl, C₅₋₇ cyclichydrocarbyl group, 5- to 7-membered monocyclic heterocyclic group,phenyl, 5- to 6-membered heteroaryl; preferably selected from the groupconsisting of H and C₁₋₄ alkyl; the alkyl, cyclic hydrocarbyl group,heterocyclic group, phenyl and heteroaryl are each optionallysubstituted by 1, 2, 3 or more R¹³.

8. The compound according to any one of items 1 to 7, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹³, at each occurrence, is independently selected fromthe group consisting of F, Cl, Br, I, amino, cyano, nitro, C₁₋₄ alkyl,C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclic heterocyclicgroup, phenyl, 5- to 6-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹,—OC(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₄ alkylene-R¹¹,—C₁₋₄ alkylene-OR¹¹, —C₁₋₄ alkylene-OC(═O)R¹¹, —C₁₋₄ alkylene-C(═O)OR¹¹,—C₁₋₄ alkylene-S(═O)_(y)OR¹¹, —C₁₋₄ alkylene-OC(═O)NR¹¹R¹², —C₁₋₄alkylene-C(═O)NR¹¹R¹², —C₁₋₄ alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄alkylene-S(═O)_(y)NR¹¹R¹²; preferably is F, Cl, Br, I, amino, cyano,nitro, C₁₋₄ alkyl, —OR¹¹ (preferably, R¹¹ is a C₁₋₆ alkyl optionallysubstituted by 1, 2, 3 or more halogens, more preferably a C₁₋₃ alkyloptionally substituted by 1, 2 or 3 F or Cl), —SR¹¹ (preferably, R¹¹ isC₁₋₆ alkyl optionally substituted by 1, 2, 3 or more halogens), morepreferably C₁₋₃ alkyl optionally substituted by 1, 2 or 3 F or Cl), orphenyl; and

preferably, wherein the alkyl, alkylene, cyclic hydrocarbyl group,heterocyclic group, phenyl and heteroaryl are optionally furthersubstituted by 1, 2, 3 or more substitutes independently selected fromthe group consisting of F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, C₅₋₆ cyclic hydrocarbyl group, 5- to7-membered monocyclic heterocyclic group, phenyl, 5- to 6-memberedheteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C₁₋₄ alkyl andhalogenated C₁₋₄ alkyl.

9. The compound according to any one of items 1, and 3 to 7, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹³, at each occurrence, is independently selected fromthe group consisting of —P(O)R¹¹R¹², wherein preferably, R¹¹ and R¹², ateach occurrence, are each independently a C₁₋₆ alkyl optionallysubstituted by 1, 2, 3 or more halogens, preferably a C₁₋₃ alkyloptionally substituted by 1, 2 or 3 F or Cl, more preferably methyl,ethyl, propyl or isopropyl, more preferably methyl; and

C₃₋₁₀ cyclic hydrocarbyl group or 3- to 10-membered heterocyclic group,which is substituted by C₁₋₆ alkyl, preferably C₃₋₇ cyclic hydrocarbylgroup or 4- to 7-membered heterocyclic group, which is substituted byC₁₋₆ alkyl, preferably C₅₋₇ cyclic hydrocarbyl group or 5- to 7-memberedmonocyclic heterocyclic group, which is substituted by C₁₋₃ alkyl,wherein the alkyl is optionally substituted by 1, 2, 3 or more OH orhalogens, preferably optionally substituted by 1, 2 or 3 OH, F or Cl.

10. The compound according to any one of items 1 to 9, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R is:

wherein

R^(1a), R^(1b) together with X¹ to which they are attached form a groupwhich is optionally substituted by 1, 2, 3 or more R¹³ and is selectedfrom the group consisting of C₅₋₇ cyclic hydrocarbyl group; 5- to10-membered heterocyclic group; C₆₋₁₀ aryl; and 5- to 10-memberedheteroaryl; and

X⁴ is a direct bond.

11. The compound according to item 10, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of formula (I-1) or formula (I′-1):

12. The compound according to item 10 or 11, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein

R^(1a), R^(1b) together with X¹ to which they are attached form a groupwhich is optionally substituted by 1, 2, 3 or more R¹³ and is selectedfrom the group consisting of C₅₋₇ cyclic hydrocarbyl group; 5-, 6- or7-membered monocyclic heterocyclic group; and phenyl.

13. The compound according to item 10 or 11, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein

R^(1a), R^(1b) together with X¹ to which they are attached form a groupwhich is optionally substituted by 1, 2, 3 or more R¹³ and is selectedfrom the group consisting of 5- to 10-membered heteroaryl (such as 5- to6-membered heteroaryl);

preferably, the heteroaryl is selected from the group consisting ofpyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, indazolyl,benzimidazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrazolopyrimidinyl,pyrazolopyridyl, imidazopyridyl, purinyl; preferably selected from thegroup consisting of pyrazolyl, pyrimidinyl, quinazolinyl andpyrazolopyrimidinyl; more preferably selected from the group consistingof

14. The compound according to any one of items 10 to 13, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹³ is a C₁₋₄ alkyl, C₆₋₁₀ aryl or —C₁₋₄ alkylene-R¹¹,which is optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, OH, amino, cyano, C₁₋₄alkyl and phenyl; and wherein R¹¹ is selected from the group consistingof a C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclicheterocyclic group, phenyl and 5- to 6-membered heteroaryl;

preferably, R¹³ is a C₁₋₄ alkyl, phenyl or —C₁₋₄-alkylene-phenyl, whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of F, Cl, Br, C₁₋₄ alkyl and phenyl.

15. The compound according to item 14, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R¹³ is a phenyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom the group consisting of F, Cl, Br and C₁₋₄ alkyl;

preferably, R¹³ is a phenyl or fluorophenyl (preferably

16. The compound according to item 14, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R¹³ is a C₁₋₄alkyl or —C₁₋₄-alkylene-phenyl, which is optionally substituted by 1, 2or 3 substituents independently selected from the group consisting ofC₁₋₄ alkyl and phenyl;

preferably, R¹³ is methyl or —CH₂-phenyl.

17. The compound according to any one of items 10 to 15, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1a), R^(1b) together with X¹ to which they areattached form a group selected from the group consisting of phenyl,

18. The compound according to any one of items 1 to 9, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R is:

wherein

R^(1a) is a group which is optionally substituted by 1, 2, 3 or more R¹³and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cyclic hydrocarbyl group, 4- to 7-membered monocyclicheterocyclic group, 8- to 10-membered benzo-fused heterocyclic group,phenyl, 5- to 10-membered heteroaryl, —C₁₋₃ alkylene-C₃₋₇ cyclichydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-membered monocyclicheterocyclic group), —C₁₋₃ alkylene-(8- to 10-membered benzo-fusedheterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃ alkylene-(5- to10-membered heteroaryl); and

R^(1b) does not exist or is selected from the group consisting of H andR^(1a).

19. The compound according to item 18, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein

R^(1a) is a group which is optionally substituted by 1, 2, 3 or more R¹³and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 4- to 7-membered monocyclicheterocyclic group (including 5-, 6- or 7-membered monocyclicheterocyclic group), 8- to 10-membered benzo-fused heterocyclic group,phenyl, 5- to 10-membered heteroaryl (including 5- to 6-memberedheteroaryl), —C₁₋₃ alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃alkylene-(5- to 7-membered monocyclic heterocyclic group), —C₁₋₃alkylenephenyl and —C₁₋₃ alkylene-(5- to 6-membered heteroaryl).

20. The compound according to any one of items 1 to 9 and 18-19, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1b) does not exist, and X¹ does not exist.

21. The compound according to item 20, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of formula (I-2) or formula (I′-2):

22. The compound according to item 20 or 21, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein X⁴is selected from the group consisting of C(═O), S(═O)_(y), —O—C(═O)—,—S—C(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, preferablyis C(═O), —O—C(═O)— or —NR¹⁰—C(═O)—.

23. The compound according to any one of items 18 and 20-22, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R^(1a) is a group selected from the group consisting of optionallysubstituted C₃₋₇ cyclic hydrocarbyl group, optionally substituted 4- to7-membered monocyclic heterocyclic group, optionally substituted 8- to10-membered benzo-fused heterocyclic group, optionally substitutedphenyl, optionally substituted 5- to 10-membered heteroaryl, -optionallysubstituted C₁₋₃ alkylene-(optionally substituted C₃₋₇ cyclichydrocarbyl group), -optionally substituted C₁₋₃ alkylene-(optionallysubstituted 5- to 7-membered monocyclic heterocyclic group), -optionallysubstituted C₁₋₃ alkylene-(optionally substituted 8- to 10-memberedbenzo-fused heterocyclic group), -optionally substituted C₁₋₃alkylene-optionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-(optionally substituted 5- to 10-membered heteroaryl);

preferably, R^(1a) is a group selected from the group consisting ofoptionally substituted C₃₋₇ cyclic hydrocarbyl group, optionallysubstituted 4- to 7-membered monocyclic heterocyclic group, optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group, optionallysubstituted phenyl, optionally substituted 5- to 10-membered heteroaryl,—C₁₋₃ alkylene-(optionally substituted C₃₋₇ cyclic hydrocarbyl group),—C₁₋₃ alkylene-(optionally substituted 5- to 7-membered monocyclicheterocyclic group), —C₁₋₃ alkylene-(optionally substituted 8- to10-membered benzo-fused heterocyclic group), -optionally substitutedC₁₋₃ alkylene-optionally substituted phenyl, and —C₁₋₃alkylene-(optionally substituted 5- to 10-membered heteroaryl);

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³;

R^(1b) does not exist;

X¹ does not exist; and

X⁴ is selected from the group consisting of C(═O), S(═O)_(y), —OC(═O)—and —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein R¹⁰ is preferably H orC₁₋₆ alkylene.

24. The compound according to item 23, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein

R^(1a) is a group selected from the group consisting of an optionallysubstituted 5-, 6- or 7-membered monocyclic heterocyclic group, anoptionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl;

preferably a group selected from the group consisting of an optionallysubstituted 5-, 6- or 7-membered monocyclic heterocyclic group, anoptionally substituted phenyl, and —C₁₋₃ alkylene-optionally substitutedphenyl; and

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³.

25. The compound according to item 23, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R^(1a) is agroup selected from the group consisting of

an optionally substituted C₃₋₇ cyclic hydrocarbyl group, wherein thecyclic hydrocarbyl group is, for example, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

an optionally substituted 4- to 7-membered monocyclic heterocyclicgroup, wherein the heterocyclic group is, for example,

an optionally substituted 8- to 10-membered benzo-fused heterocyclicgroup, wherein the heterocyclic group is, for example,

an optionally substituted phenyl;

-   -   optionally substituted C₁₋₃ alkylene-optionally substituted        phenyl;

an optionally substituted 5- to 10-membered heteroaryl, and —C₁₋₃alkylene-(optionally substituted 5- to 10-membered heteroaryl), whereinthe heteroaryl is, for example,

and

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³.

26. The compound according to any one of items 23 to 25, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹³ is selected from the group consisting of halogen,OH, —NR¹¹R¹², cyano and C₁₋₄ alkyl; and phenyl, 5-, 6- or 7-memberedmonocyclic heterocyclic group and 5- to 6-membered heteroaryl, which areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom the group consisting of halogen, OH, —NR¹¹R¹², cyano and C₁₋₄alkyl, and wherein R¹¹ and R¹² are each independently selected from thegroup consisting of H and C₁₋₄ alkyl (preferably methyl);

preferably, R¹³ is selected from the group consisting of F, Cl, Br,—N(CH₃)₂, and C₁₋₄ alkyl; and phenyl, 5- to 7-membered monocyclicheterocyclic group (such as

and 5- to 6-membered heteroaryl (such as

which are optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of F, Cl, Br and C₁₋₄ alkyl.

27. The compound according to any one of items 23 to 26, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1a) is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

28. The compound according to any one of items 23 to 27, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁴ is selected from the group consisting of C(═O),S(═O)_(y) and —O—C(═O)—, and wherein y is preferably 2.

29. The compound according to any one of items 23 to 28, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R³ is COOH,

and R⁴ is H.

30. The compound according to item 20 or 21, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein X⁴is a direct bond.

31. The compound according to item 30, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R^(1a) is —C₁₋₃alkylenephenyl, preferably —CH₂-phenyl.

32. The compound according to item 22, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R^(1a) is selected from the group consisting of C₂₋₆ alkenyl (preferablyvinyl, 1-propenyl or 2-propenyl) and C₂₋₆ alkynyl (preferably ethynyl,1-propynyl or 2-propynyl), which are optionally substituted by 1, 2, 3or more R¹³; and

X⁴ is C(═O) or —O—C(═O)—.

33. The compound according to item 32, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R¹³ is selected from the group consisting of phenyl and 5- to 6-memberedheteroaryl, which are optionally substituted by 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, OH, amino,cyano and C₁₋₄ alkyl;

preferably, R¹³ is a phenyl or pyridyl, which is optionally substitutedby 1, 2 or 3 substituents independently selected from the groupconsisting of F, Cl and Br.

34. The compound according to item 32 or 33, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, whereinR^(1a) is selected from the group consisting of

35. The compound according to any one of items 1-9 and 18-19, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CR¹⁰ or N.

36. The compound according to item 35, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁴ is a directbond.

37. The compound according to item 35, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁴ is selectedfrom the group consisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(r), preferably is C(═O),—O—C(═O)— or —NR¹⁰—C(═O)—.

38. The compound according to any one of items 35 to 37, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1b) is selected from the group consisting of H andR^(1a), and preferably, X¹ is CH.

39. The compound according to item 36, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R^(1a) is selected from the group consisting of C₂₋₆ alkenyl (such asvinyl, 1-propenyl or 2-propenyl) and C₂₋₆ alkynyl (such as ethynyl,1-propynyl or 2-propynyl) which are optionally substituted by 1, 2, 3 ormore R¹³; and/or

R^(1b) is selected from the group consisting of C₁₋₄ alkyl optionallysubstituted by 1, 2, 3 or more R¹³.

40. The compound according to item 39, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R¹³ is selected from the group consisting of C₁₋₄ alkyl, phenyl and 5-to 6-membered heteroaryl, which are optionally substituted by 1, 2 or 3substituents independently selected from the group consisting ofhalogen, OH, amino, cyano and C₁₋₄ alkyl;

preferably, R¹³ is a C₁₋₄ alkyl or phenyl, which is optionallysubstituted by 1, 2 or 3 substituents independently selected from thegroup consisting of F, C₁ and Br;

more preferably, R¹³ is a C₁₋₄ alkyl (such as methyl, ethyl, propyl,isopropyl or tert-butyl); or a phenyl optionally substituted by 1, 2 or3 substituents independently selected from the group consisting of F, Cland Br.

41. The compound according to item 39 or 40, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein:

R^(1a) is

and/or

R^(1b) is methyl, ethyl, n-propyl or isopropyl.

42. The compound according to any one of items 39 to 41, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CH or N, preferably CH.

43. The compound according to item 37, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R^(1a) is a group selected from the group consisting of an optionallysubstituted C₃₋₇ cyclic hydrocarbyl group, an optionally substituted 4-to 7-membered monocyclic heterocyclic group, an optionally substituted8- to 10-membered benzo-fused heterocyclic group, an optionallysubstituted phenyl, an optionally substituted 5- to 10-memberedheteroaryl, -optionally substituted C₁₋₃ alkylene-(optionallysubstituted C₃₋₇ cyclic hydrocarbyl group), -optionally substituted C₁₋₃alkylene-(optionally substituted 5- to 7-membered monocyclicheterocyclic group), -optionally substituted C₁₋₃ alkylene-(optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group),-optionally substituted C₁₋₃ alkylene-optionally substituted phenyl, and-optionally substituted C₁₋₃ alkylene-(optionally substituted 5- to10-membered heteroaryl);

preferably, R^(1a) is a group selected from the group consisting of anoptionally substituted C₃₋₇ cyclic hydrocarbyl group, an optionallysubstituted 4- to 7-membered monocyclic heterocyclic group, anoptionally substituted 8- to 10-membered benzo-fused heterocyclic group,an optionally substituted phenyl, an optionally substituted 5- to10-membered heteroaryl, —C₁₋₃ alkylene-(optionally substituted C₃₋₇cyclic hydrocarbyl group), —C₁₋₃ alkylene-(optionally substituted 5- to7-membered monocyclic heterocyclic group), —C₁₋₃ alkylene-(optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group), —C₁₋₃alkylene-optionally substituted phenyl, and —C₁₋₃ alkylene-(optionallysubstituted 5- to 10-membered heteroaryl); and

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³.

44. The compound according to item 43, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R^(1a) is agroup selected from the group consisting of

an optionally substituted phenyl;

—C₁₋₃ alkylene-(optionally substituted C₃₋₇ cyclic hydrocarbyl group),the cyclic hydrocarbyl group being, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl;

—C₁₋₃ alkylene-(optionally substituted 8- to 10-membered benzo-fusedheterocyclic group), the heterocyclic group being, for example,

—C₁₋₃ alkylene-optionally substituted phenyl;

an optionally substituted 5- to 10-membered heteroaryl and —C₁₋₃alkylene-(optionally substituted 5- to 10-membered heteroaryl), theheteroaryl being, for example,

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³.

45. The compound according to item 43 or 44, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, whereinR¹³ is selected from the group consisting of halogen, —OR¹¹ (preferably,R¹¹ is C₁₋₆ alkyl optionally substituted by 1, 2, 3 or more halogens,more preferably C₁₋₃ alkyl optionally substituted by 1, 2 or 3 F or Cl),—NR¹¹R¹², cyano and C₃₋₇ cyclic hydrocarbyl group; and C₁₋₄ alkyl, C₂₋₄alkenyl and C₂₋₄ alkynyl which are optionally substituted by 1, 2, 3 ormore halogens, and wherein R¹¹ and R¹² are each independently selectedfrom the group consisting of H and C₁₋₄ alkyl (preferably methyl);

preferably, R¹³ is selected from the group consisting of F, Cl, Br, OH,—OC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, cyano, C₃₋₇ cyclic hydrocarbyl group,C₂₋₄ alkenyl and C₂₋₄ alkynyl; and C₁₋₄ alkyl optionally substituted by1, 2, 3 or more F, Cl or Br;

more preferably, R¹³ is selected from the group consisting of F, Cl, Br,—OCH₃, —N(CH₃)₂, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl,ethynyl, 1-propenyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl,tert-butyl and CF₃; or

R¹³ is as defined in item 9.

46. The compound according to item 43 or 44, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, whereinR^(1a) is selected from the group consisting of

47. The compound according to any one of items 43 to 46, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1b) is a group selected from the group consisting ofH, an optionally substituted C₁₋₄ alkyl, an optionally substituted C₃₋₇cyclic hydrocarbyl group, an optionally substituted phenyl, -optionallysubstituted C₁₋₃ alkylene-(optionally substituted C₃₋₇ cyclichydrocarbyl group), and -optionally substituted C₁₋₃ alkylene-optionallysubstituted phenyl;

preferably, R^(1b) is a group selected from the group consisting of H,an optionally substituted C₁₋₄ alkyl, an optionally substituted C₃₋₇cyclic hydrocarbyl group, an optionally substituted phenyl, —C₁₋₃alkylene-(optionally substituted C₃₋₇ cyclic hydrocarbyl group), and—C₁₋₃ alkylene-optionally substituted phenyl;

more preferably, R^(1b) is a group selected from the group consisting of

H, phenyl;

an optionally substituted C₁₋₄ alkyl, the alkyl being, for example,methyl, ethyl or isopropyl;

an optionally substituted C₃₋₇ cyclic hydrocarbyl group and —C₁₋₃alkylene-(C₃₋₇ cyclic hydrocarbyl group), the cyclic hydrocarbyl groupbeing, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;and

—C₁₋₃ alkylene-phenyl; and

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³;

wherein R¹³ is preferably selected from the group consisting of halogenand C₁₋₄ alkyl, more preferably selected from the group consisting of F,Cl, Br and methyl.

48. The compound according to item 47, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R^(1b) isselected from the group consisting of H, methyl, ethyl, isopropyl,CF₃CH₂, cyclopropyl,

phenyl,

49. The compound according to any one of items 43 to 48, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CFI or N, preferably N.

50. The compound according to any one of items 43 to 49, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁴ is selected from the group consisting of C(═O) andS(═O)_(y), and wherein y is preferably 2.

51. The compound according to any one of items 43 to 50, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R³ is COOH or

and R⁴ is H.

52. The compound according to any one of items 1 to 51, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein:

R^(2a) is selected from the group consisting of an optionallysubstituted phenyl, and -optionally substituted C₁₋₃ alkylene-optionallysubstituted phenyl;

preferably, R^(2a) is selected from the group consisting of anoptionally substituted phenyl, and —C₁₋₃ alkylene-optionally substitutedphenyl; and/or

R^(2b) is selected from the group consisting of an optionallysubstituted C₁₋₄ alkyl, an optionally substituted phenyl, and-optionally substituted C₁₋₃ alkylene-optionally substituted phenyl;

preferably, R^(2b) is selected from the group consisting of C₁₋₄ alkyl,an optionally substituted phenyl, and —C₁₋₃ alkylene-optionallysubstituted phenyl;

wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³.

53. The compound according to item 52, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R¹³ is selectedfrom the group consisting of halogen and —OR¹¹, and wherein R¹¹ isselected from C₁₋₄ alkyl (preferably methyl);

preferably, R¹³ is selected from the group consisting of F, Cl, Br and—OCH₃.

54. The compound according to item 52 or 53, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein:

R^(2a) is selected from the group consisting of phenyl,

and/or

R^(2b) is selected from the group consisting of methyl, phenyl,

55. The compound according to any one of items 43 to 54, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein the compound has a structure of formula (II) or formula(III):

wherein R^(1a), R^(1b), X¹, X⁴, R^(2a), R^(2b), X², R³, R⁴, h and k areas defined in any one of items 43 to 54.

56. The compound according to any one of items 1 to 9, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R is:

wherein

R^(1a) is a group which is optionally substituted by 1, 2, 3 or more R¹³and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5-, 6- or 7-memberedmonocyclic heterocyclic group, 8- to 10-membered benzo-fusedheterocyclic group, phenyl, 5- to 6-membered heteroaryl, —C₁₋₃alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-memberedmonocyclic heterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃alkylene-(5- to 6-membered heteroaryl);

R^(1b) and X¹ together form a bivalent C₅₋₇ cyclic hydrocarbyl group ora bivalent 5-, 6- or 7-membered monocyclic heterocyclic group; and

X⁴ is selected from the group consisting of C(═O) and S(═O)_(y).

57. The compound according to item 56, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein:

R^(1a) is phenyl; and

R^(1b) and X¹ together form

58. The compound according to any one of items 18 to 22, 35 to 38, and56 to 57, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein R¹³ is selected from the group consisting ofC₁₋₄ alkyl-O—; halogen (including F, Cl, Br and I); and C₁₋₄ alkyl orphenyl, which is optionally substituted by 1, 2 or 3 substituentsindependently selected from halogen.

59. The compound according to any one of items 10 to 12, 14 to 16, 18 to24, 26, 31 to 33, 39 to 40, 43, 45, 47, 52 to 53, 56 and 58, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein:

the alkyl is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-hexyl, 1-heptyl, 1-octyl;

the alkenyl is selected from the group consisting of vinyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and2-hexenyl;

the alkynyl is selected from the group consisting of ethynyl,1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 2-hexynyl and 3-hexynyl;

the —C₁₋₃ alkylenephenyl is selected from the group consisting of benzyland phenethyl;

the cyclic hydrocarbyl group is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

the monocyclic heterocyclic group is selected from the group consistingof tetrahydrofuranyl, tetrahydro thienyl, pyrrolidinyl (e.g.pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl,1,3-dioxolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl(such as morpholino)), thiomorpholinyl, tetrahydro-2H-pyranyl,tetrahydro-2H-thiopyranyl, 1,3-oxazinanyl (1,3-oxazinane),1,3-thiazinanyl (1,3-thiazinane), hexahydropyrimidyl, 1,3-oxathianyl(1,3-oxathiane), 1,4-oxathianyl (1,4-oxathiane), 1,3-diazepanyl(1,3-diazepane), 1,4-diazepanyl (1,4-diazepane), 1,3-oxazepanyl(1,3-oxazepane), 1,3-thiazepanyl (1,3-thiazepane);

the heteroaryl is selected from the group consisting of thienyl, furyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (such as1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pryazolyl), isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and/or

the benzo-fused heterocyclic group is selected from the group consistingof

60. The compound according to any one of items 1 to 59, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R is:

61. The compound according to any one of items 1 to 9, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein Y is a single bond, NR¹⁰, O, S, methylene, ethylene,—CH₂—O—, —O—CH₂—, —CH₂—S—, —S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—, —CH═CH—,—CH═N— or —N═CH—.

62. The compound according to any one of items 1 to 9 and 61, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R is

and

the optionally substituted saturated or partially unsaturated fused ringsystem comprising 3 or more rings which is formed by R^(1a) and R^(1b)together with X¹ to which they are attached has a structure of formula(a):

wherein:

ring A and ring B are each independently C₃₋₁₀ cyclic hydrocarbyl group,3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, or 5- to 14-memberedheteroaryl, preferably C₅₋₇ cyclic hydrocarbyl group (such as,cyclopentyl or cyclohexyl), 5- to 7-membered monocyclic heterocyclicgroup, phenyl, or 5- to 6-membered heteroaryl;

represents a single bond or a double bond;

preferably the fused ring system has a structure of formula (1) orformula (2):

wherein

R^(5a) and R^(5b), at each occurrence, are each independently R¹⁰;

R⁷ does not exist or is R¹⁰; and

m and n, at each occurrence, are each independently 0, 1, 2 or 3.

63. The compound according to any one of items 1 to 9 and 61 to 62, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CH or N.

64. The compound according to item 62 or 63, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein:

the group of formula (1) has a structure selected from the groupconsisting of

the group of formula (2) has a structure selected from the groupconsisting of

65. The compound according to any one of items 1 to 9, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R is:

and

X⁶ is selected from the group consisting of O, S, NR¹⁰, —C(═O)—NR¹⁰— and—S(═O)_(y)—NR¹⁰—, preferably selected from the group consisting of O, S,NH, N(C₁₋₆ alkyl), —C(═O)—NH—, —C(═O)—N(C₁₋₆ alkyl)-, —S(═O)_(y)—NH— and—S(═O)_(y)—N(C₁₋₆ alkyl)-, more preferably selected from the groupconsisting of O, S, NH, N(C₁₋₄ alkyl) and —C(═O)—NH—, even morepreferably selected from the group consisting of O, S, NH, N(CH₃) and—C(═O)—NH—; and/or

R⁹ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclicheterocyclic group, phenyl, 5- to 6-membered heteroaryl and phenyl-C₁₋₆alkylene-, preferably selected from the group consisting of H, C₁₋₄alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl), C₂₋₄ alkenyl (including vinyl, 1-propenyl,2-propenyl, 2-butenyl and 3-butenyl), C₂₋₄ alkynyl (including ethynyl,1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl), phenyl and phenyl-C₁₋₄alkylene-(including phenyl-methylene- and phenyl-ethylene-);

the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl group,heterocyclic group, aryl and heteroaryl are each optionally substitutedby 1, 2, 3 or more R¹³;

R¹³ is as defined in any one of items 1 to 9;

preferably, R¹³, at each occurrence, is independently selected from thegroup consisting of halogen (including F, Cl, Br, and I); OH; amino;cyano; nitro; and C₁₋₆ alkyl (including C₁₋₄ alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl)and C₆₋₁₀ aryl (such as phenyl), which are optionally substituted by 1,2, 3 or more substituents independently selected from the groupconsisting of halogen (including F, Cl, Br, and I), OH, amino, cyano,nitro and phenyl.

66. The compound according to item 65, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R⁹ isphenyl-C₁₋₄ alkylene-.

67. The compound according to item 65, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R is selectedfrom the group consisting of:

68. The compound according to any one of items 65 to 67, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁶ is selected from the group consisting of O and S,preferably is O.

69. The compound according to any one of items 65 to 68, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X³ is CH.

70. The compound according to any one of items 1 to 51 and 56 to 69, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R^(2a), R^(2b) together with X² to which they are attached form a groupwhich is optionally substituted by 1, 2, 3 or more R¹³ and is selectedfrom the group consisting of C₅₋₇ cyclic hydrocarbyl group; 5-, 6- or7-membered monocyclic heterocyclic group; phenyl; and 5- to 6-memberedheteroaryl; and

X⁵ is a direct bond.

71. The compound according to item 70, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R¹³ is C₁₋₄alkyl or phenyl-C₁₋₄-alkyl-, which is optionally substituted by 1, 2 or3 substituents independently selected from the group consisting of C₁₋₄alkyl and phenyl.

72. The compound according to any one of items 1 to 51 and 56 to 69, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R^(2a) is a group which is optionally substituted by 1, 2, 3 or more R¹³and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5-, 6- or 7-memberedmonocyclic heterocyclic group, 8- to 10-membered benzo-fusedheterocyclic group, phenyl, 5- to 6-membered heteroaryl, —C₁₋₃alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-memberedmonocyclic heterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃alkylene-(5- to 6-membered heteroaryl); and

R^(2b) does not exist or is selected from the group consisting of H andR^(2a).

73. The compound according to any one of items 1 to 51, 56 to 69 and 72,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(2b) does not exist, and X² does not exist.

74. The compound according to item 73, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁵ is selectedfrom the group consisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, preferably is C(═O),—O—C(═O)— or —NR¹⁰—C(═O)—.

75. The compound according to any one of items 70 to 74, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R^(2a) is a group selected from the group consisting of an optionallysubstituted 5-, 6- or 7-membered monocyclic heterocyclic group, anoptionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl, wherein the term “optionallysubstituted” means being substituted by 1, 2, 3 or more R¹³;

R^(2b) does not exist;

X² does not exist; and

X⁵ is selected from the group consisting of C(═O), S(═O)_(y), —OC(═O)—and —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein R¹⁰ is preferably H orC₁₋₆ alkylene.

76. The compound according to any one of items 1 to 69 and 72, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X² is CR¹⁰ or N, and wherein R¹⁰ is preferably H, OH orC₁₋₄ alkyl (such as methyl).

77. The compound according to item 76, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁵ is a directbond.

78. The compound according to item 76, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁵ is selectedfrom the group consisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(r), preferably is C(═O),—O—C(═O)— or —NR¹⁰—C(═O)—.

79. The compound according to any one of items 76 to 78, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(2b) is selected from the group consisting of H andR^(2a), and preferably, X² is CH.

80. The compound according to any one of items 1 to 51 and 56 to 69, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

R^(2a) is a group which is optionally substituted by 1, 2, 3 or more R¹³and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5-, 6- or 7-memberedmonocyclic heterocyclic group, 8- to 10-membered benzo-fusedheterocyclic group, phenyl, 5- to 6-membered heteroaryl, —C₁₋₃alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-memberedmonocyclic heterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃alkylene-(5- to 6-membered heteroaryl);

R^(2b) and X² together form a bivalent C₅₋₇ cyclic hydrocarbyl group ora bivalent 5-, 6- or 7-membered monocyclic heterocyclic group; and

X⁵ is selected from the group consisting of C(═O) and S(═O)_(y).

81. The compound according to any one of items 72 to 80, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹³ is selected from the group consisting of C₁₋₄alkyl-O—; halogen (including F, Cl, Br, and I); and C₁₋₄ alkyl orphenyl, which is optionally substituted by 1, 2 or 3 substituentsindependently selected from halogen.

82. The compound according to any one of items 70 to 81, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein:

the alkyl is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-hexyl, 1-heptyl, 1-octyl;

the alkenyl is selected from the group consisting of vinyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and2-hexenyl;

the alkynyl is selected from the group consisting of ethynyl,1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 2-hexynyl and 3-hexynyl; the cyclic hydrocarbyl group isselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl;

the monocyclic heterocyclic group is selected from the group consistingof tetrahydrofuranyl, tetrahydro thienyl, pyrrolidinyl (e.g.pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl,1,3-dioxolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl(such as morpholine)), thiomorpholinyl, tetrahydro-2H-pyranyl,tetrahydro-2H-thiopyranyl, 1,3-oxazinanyl (1,3-oxazinane),1,3-thiazinanyl (1,3-thiazinane), hexahydropyrimidyl, 1,3-oxathianyl(1,3-oxathiane), 1,4-oxathianyl (1,4-oxathiane), 1,3-diazepanyl(1,3-diazepane), 1,4-diazepanyl (1,4-diazepane), 1,3-oxazepanyl(1,3-oxazepane), 1,3-thiazepanyl (1,3-thiazepane);

the heteroaryl is selected from the group consisting of thienyl, furyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (such as1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pryazolyl), isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;

the benzo-fused heterocyclic group is selected from the group consistingof

the —C₁₋₃ alkylenephenyl is selected from the group consisting of benzyland phenethyl.

83. The compound according to any one of items 1 to 51 and 56 to 82, orthe pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R′ is:

84. The compound according to any one of items 1 to 51 and items 56 to69, or the pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein Z is a single bond, NR¹⁰, O, S, methylene,ethylene, —CH₂—O—, —O—CH₂—, —CH₂—S—, —S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—,—CH═CH—, —CH═N— or —N═CH—.

85. The compound according to any one of items 1 to 51, 56 to 69 and 84,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein

the optionally substituted saturated or partially unsaturated fused ringsystem comprising 3 or more rings which is formed by R^(2a) and R^(2b)together with X² to which they are attached has a structure of formula(b):

wherein:

ring C and ring D are each independently C₃₋₁₀ cyclic hydrocarbyl group,3- to 10-membered heterocyclic group, C₆₋₁₀ aryl or 5- to 14-memberedheteroaryl, preferably C₅₋₇ cyclic hydrocarbyl group, 5- to 7-memberedmonocyclic heterocyclic group, phenyl or 5- to 6-membered heteroaryl;

“

” represents a single bond or a double bond;

preferably, the fused ring system has a structure of formula (3) orformula (4):

wherein

R^(6a) and R^(6b), at each occurrence, are each independently R¹⁰;

R⁸ does not exist or is R¹⁰; and

p and q, at each occurrence, are each independently 0, 1, 2 or 3.

86. The compound according to any one of items 1 to 69 and 84 to 85, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X², at each occurrence, is independently CR¹⁰ or N, andwherein R¹⁰ is H, OH, amino or C₁₋₄ alkyl (such as methyl).

87. The compound according to item 85 or 86, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein:

the group of formula (3) has a structure selected from the groupconsisting of

or

the group of formula (4) has a structure selected from the groupconsisting of

88. The compound according to any one of items 1 to 10, 12 to 20, 22 to54 and 56 to 87, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein:

the compound has a structure of formula (I-a) or formula (I″-a):

particularly, the structure of formula (IV) or formula (V):

or

the structure of formula (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7)or (a-8):

or

the compound has a structure of formula (I-b) or formula (I′-b):

particularly, the structure of formula (b-1). (b-2). (b-3) or (b-4):

89. The compound according to item 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of

No. Structure C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

C19

C20

C21

C22

C23

C24

C25

C26

C27

C28

C29

C30

C31

C32

C33

C34

C35

C36

C37

C38

C39

C40

C41

C42

C43

C44

C45

C46

C47

C48

C49

C50

C51

C52

C53

C54

C55

C56

C57

C58

C59

C60

C61

C62

C63

C64

C65

C66

C67

C68

C69

C70

C71

C72

C73

C74

C75

C76

C77

C78

C79

C80

C81

C82

C83

C84

C85

C86

C87

C88

C89

C90

C91

C92

C93

C94

C95

C96

C97

C98

C99

C100

C101

C102

C103

C104

C105

C106

C107

C108

C109

C110

C111

C112

C113

C114

C115

C116

C117

C118

C119

C120

C121

C122

C123

C124

C125

C126

C127

C128

C129

C130

C131

C132

C133

C134

C135

C136

C137

C138

C139

C140

C141

C142

C143

C144

C145

C146

C147

C148

C149

C150

C151

C152

C153

C154

C155

C156

C157

C158

C159

C160

C161

C162

C163

C164

C165

C166

C167

C168

C169

C170

C171

C172

C173

C174

C177

C178

C179

C180

C181

C182

C183

C184

C185

C186

C187

C188

C189

C190

C191

C192

C193

C194

C195

C196

C197

C198

C199

C200

C201

C202

C203

C204

C205

C206

C207

C208

C209

C210

C211

C212

C213

C214

C215

C216

C217

C218

C219

C220

C221

C222

C223

C224

C225

C226

C227

C228

C229

C230

C231

C232

C233

C234

C235

C236

C237

C238

C239

C240

C241

C242

C243

C244

C245

C246

C247

C248

C249

C250

C251

C252

C253

C254

C255

C256

C257

C258

C259

C260

C261

C262

C263

C264

C265

C266

C267

C268

C269

C270

C271

C272

C273

C274

C275

C276

C277

C278

C279

C280

C281

C282

C283

C284

C285

C286

C287

C288

C289

C290

C291

C292

C293

C294

C295

C296

C297

C298

C299

C300

C301

C302

C303

C304

C305

C306

C307

C308

C309

C310

C311

C312

C313

C314

C315

C316

C317

C318

C319

In some embodiments, the compound of the present invention has selectiveinhibitory activity on AT₂ receptors, compared to AT₁ receptors.

Pharmaceutical Composition and Therapeutic Method

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a prophylactically or therapeutically effectiveamount of the compound of the present invention or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof and one ormore pharmaceutically acceptable carriers, and the pharmaceuticalcomposition is preferably in the form of a solid, semi-solid, liquid, orgas preparation. In some embodiments, the pharmaceutical composition canfurther comprise one or more additional therapeutic agents.

In some embodiments, the present invention provides use of the compoundof the present invention or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof or the pharmaceuticalcomposition of the present invention in the manufacture of a medicamentfor use as an angiotensin II type 2 (AT₂) receptor inhibitor.

In some embodiments, the present invention provides the compound of thepresent invention or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof or the pharmaceuticalcomposition of the present invention for use as an angiotensin II type 2(AT₂) receptor inhibitor.

In some embodiments, the present invention provides a method for theprophylaxis or the treatment of an AT₂ receptor-mediated disorder or asymptom associated therewith, comprising administering to a subject inneed thereof an effective amount of the compound of the presentinvention or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, or the pharmaceutical composition of the presentinvention.

In some embodiments, the AT2 receptor-mediated disorder is selected fromcerebrovascular disorders (including cerebrovascular spasm and cerebralischemia); cognitive disorders (including amnesia, senile dementia, AIDSrelated dementia and Down's syndrome); central nervous system diseasesor disorders (including addiction such as alcoholism, anxiety,depression or dysthymic disorders, epilepsy, hyperactivity, pain,Parkinson's disease, psychosis, sleep disorders, irregular autonomicfunction, and tardive dyskinesia, schizophrenia, demyelinating diseasessuch as multiple sclerosis and amyotrophic lateral sclerosis);respiratory diseases (including bronchospasm, asthma, chronicobstructive airways disease), neural tumors; inflammatory diseases(including inflammatory bowel disease and osteoarthritis);gastrointestinal (GI) diseases or disorders (including ulcerativecolitis, Crohn's disease and incontinence); disorders of blood flowcaused by vasodilation; hypersensitivity disorders (including allergiessuch as eczema, rhinitis and contact dermatitis); vasospastic diseases(including angina, migraine and Reynaud's disease); fibrosing andcollagen diseases (including scleroderma and eosinophilic fascioliasis);reflex sympathetic dystrophy (including shoulder/hand syndrome); stressrelated somatic disorders; peripheral neuropathy; neuralgia; autoimmunedisease (including systemic lupus erythematosus, rheumatoid arthritis,psoriasis and graft versus host disease); and rheumatic diseases(including fibrositis).

In some embodiments, the AT2 receptor-mediated disorder is selected from

neuropathic conditions (including primary neuropathy and secondaryneuropathy, such as peripheral neuropathy) or symptoms associated withthe same (including hyperesthesia, hyperalgesia, allodynia, spontaneousburning pain, numbness, weakness, burning pain, shooting pain, and lossof reflexes), preferably neuropathic pain; wherein the secondaryneuropathy includes diabetic neuropathy; Herpes Zoster-relatedneuropathy; uremia-associated neuropathy; amyloidosis neuropathy; HIVsensory neuropathies; hereditary motor and sensory neuropathies;hereditary sensory neuropathies; hereditary sensory and autonomicneuropathies; hereditary neuropathies with ulcero-mutilation;nitrofurantoin neuropathy; tomaculous neuropathy; neuropathy caused bynutritional deficiency; neuropathy caused by kidney failure and complexregional pain syndrome; neuropathes caused by repetitive activities(such as typing or working on an assembly line); peripheral neuropathiescaused by antiretroviral drags (such as zalcitabine and didanosine),antibiotics (such metronidazole and isoniazid), gold compounds,chemotherapy drugs (such as vincristine), alcohol, lead, arsenic,mercury and organophosphate pesticides; peripheral neuropathiesassociated with infectious processes (such as Guillian-Barre syndrome);

a condition characterized by neuronal hypersensitivity, including ahyperalgesic condition such as fibromyalgia and irritable bowelsyndrome;

a disorder associated with aberrant nerve regeneration, includingneuronal hypersensitivity, breast pain, interstitial cystitis,vulvodynia, a cancer chemotherapy-induced neuropathy;

inflammatory pain that can be due to conditions that are characterizedby inflammation (including burns such as chemical, frictional or thermalburns; autoimmune diseases such as rheumatoid arthritis; inflammatorybowel disease such as Crohn's disease and colitis; osteoarthritis,carditis, dermatitis, myositis, neuritis and collagen vasculardiseases);

impaired nerve conduction velocity which may be associated with aneuropathic condition as described above (such as a peripheralneuropathy) as well as Carpel Tunnel Syndrome, ulnar neuropathy,Guillian-Barre Syndrome, fascioscapulohumeral muscular dystrophy andspinal disc herniation;

a cell proliferative disorder, including a cancer (including leukaemia,melanoma, prostate cancer, breast cancer, ovarian cancer, basal cellcarcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer,lung cancer); and a non-cancerous proliferative disorder (includingdermatological disorders such as warts, keloids, psoriasis, proud fleshdisorder and also the reduction in scar tissue and cosmeticremodelling);

a disorder associated with an imbalance between bone resorption and boneformation, including osteoporosis.

In some embodiments, the present invention provides a method forregulating a reproductive function associated with AT₂ receptors in afemale patient, comprising administering to a subject in need thereof aneffective amount of the compound of the present invention or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, or the pharmaceutical composition of the present invention. Insome embodiments, the reproductive function is selected from themenstrual cycle, fertility, and hormonal balances of the estrus cycle.

The term “pharmaceutically acceptable carrier” in the present inventionrefers to a diluent, auxiliary material, excipient, or vehicle withwhich a therapeutic is administered, and it is, within the scope ofsound medical judgment, suitable for contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The pharmaceutically acceptable carrier which can be employed in thepharmaceutical composition of the present invention includes, but is notlimited to sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water is an exemplarycarrier when the pharmaceutical composition is administeredintravenously. Physiological salines as well as aqueous dextrose andglycerol solutions can also be employed as liquid carriers, particularlyfor injectable solutions. Suitable pharmaceutical excipients includestarch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel,sodium stearate, glycerol monostearate, talc, sodium chloride, driedskim milk, glycerol, propylene glycol, water, ethanol and the like. Thepharmaceutical composition, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents. Oralformulations can include standard carriers such as pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, sodium saccharine,cellulose, magnesium carbonate, etc. Examples of suitable pharmaceuticalcarriers are described in e.g. Remington's Pharmaceutical Sciences(1990).

The pharmaceutical composition of the present invention can actsystemically and/or topically. To this end, it can be administeredthrough a suitable route, such as through injection, (intravenous,intraarterial, subcutaneous, intraperitoneal, intramuscular injection,including dripping), or transdermal administration, or administered viaoral, buccal, nasal, transmucosal, topical, as an ophthalmicformulation, or via inhalation.

For these routes of administration, the pharmaceutical composition ofthe present invention can be administered in a suitable dosage form.

Such dosage forms include, but are not limited to tablets, capsules,lozenges, hard candies, powders, sprays, creams, salves, suppositories,gels, pastes, lotions, ointments, aqueous suspensions, injectablesolutions, elixirs, and syrups.

As used herein, the term “effective amount” refers to the amount of acompound being administered which will relieve to some extent one ormore of the symptoms of the disorder being treated.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time, or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It is to be noted that dosage values may vary with the typeand severity of the condition to be alleviated, and may include singleor multiple doses. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecomposition.

The amount of the compound of the present invention administered will bedependent on the subject being treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. Generally, an effectivedosage is in the range of about 0.0001 to about 50 mg per kg body weightper day, for example about 0.01 to about 10 mg/kg/day, in single ordivided doses. For a 70 kg human, this would amount to about 0.007 mg toabout 3500 mg/day, for example about 0.7 mg to about 700 mg/day. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases, still larger doses maybe employed without causing any harmful side effect, provided that suchlarger doses are first divided into several small doses foradministration throughout the day.

The content or dosage of the compound of the present invention in thepharmaceutical composition is about 0.01 mg to about 1000 mg, suitably0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg,particularly preferably 1-50 mg, e.g., 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg,etc.

Unless otherwise indicated, the term “treating” or “treatment”, as usedherein, means reversing, alleviating, inhibiting the progress of, orpreventing the disorder or condition to which such term applies, or oneor more symptoms of such disorder or condition.

As used herein, the term “subject” includes a human or non-human animal.An exemplary human subject includes a human subject having a disease(such as one described herein) (referred to as a patient), or a normalsubject. The term “non-human animal” as used herein includes allvertebrates, such as non-mammals (e.g. birds, amphibians, reptiles) andmammals, such as non-human primates, livestock and/or domesticatedanimals (such as sheep, dog, cat, cow, pig and the like).

In some embodiments, the pharmaceutical composition of the presentinvention can further comprise one or more additional therapeutic agentsor prophylactic agents.

EXAMPLES

The present invention is further described with reference to thefollowing examples, which are not provided to limit the scope of thepresent invention.

The structure of the compound was confirmed by nuclear magneticresonance spectrum (¹H NMR) or mass spectrum (MS).

Chemical shifts (δ) are expressed in parts per million (ppm). ¹H NMR wasrecorded on a Broker 400 spectrometer, the test solvent was deuteratedmethanol (CD₃OD), deuterated chloroform (CDCl₃) or hexadeuterateddimethyl sulfoxide (DMSO-d₆), and the internal standard wastetramethylsilane (TMS).

The LC-MS assay was conducted on Agilent LC-MS—1110 liquidchromatography-mass spectrometer, Agilent LC-MS—6110 liquidchromatography-mass spectrometer, Agilent LC-MS—6120 liquidchromatography-mass spectrometer (Manufacturer: Agilent) or ShimadzuLC-MS—2020.

Preparative high-performance liquid chromatography was conducted on MSinduced AutoPurification system (Waters), Gilson GX-281 (Gilson), orsemi-preparative liquid chromatograph (Tong Heng Innovation TechnologyCo., Ltd., LC3000 (Ddlsogel, C18, 30 mm×250 mm 10 μm).

Thin layer chromatography (TLC) was performed with Huanghai HSGF 254(5×20 cm) silica gel plates, and preparative thin layer chromatographywas performed with GF 254 (0.4˜0.5 nm) silica gel plates produced inYantai.

The reaction was monitored by thin layer chromatography (TLC) or LC-MS,the developing solvent system included dichloromethane and methanolsystem, n-hexane and ethyl acetate system, as well as petroleum etherand ethyl acetate system, and was adjusted (by adjusting the volumeratio of the solvents, or by adding triethylamine, etc.) according tothe polarity of the compound to be separated.

The microwave reaction was conducted by CEM Discovery Sp (400 W, RT˜300°C.) microwave reactor.

Silica gel (200-300 mesh) produced by Yucheng Chemical Co., Ltd wasnormally employed as a stationary phase in column chromatography. Theeluent system included dichloromethane and methanol system, as well asn-hexane and ethyl acetate system, and was adjusted (by adjusting thevolume ratio of the solvents, or by adding triethylamine, etc.)according to the polarity of the compound to be separated.

In the following examples, unless otherwise specified, the reactiontemperature was room temperature (20° C.˜30° C.).

The reagents employed in the Examples were purchased from companies suchas Aldrich Chemical Company, Shanghai Bide Pharmatech Co. Ltd., BeijingGreenchem Co. Ltd., Shanghai Shaoyuan Co. Ltd. or Ables Technology Co.Ltd. etc.

The abbreviations as used in the present invention have the followingmeanings:

Abbreviation Meaning CH₃CN acetonitrile (Boc)₂O di-tert-butyldicarbonate BTC triphosgene DCM dichloromethane DMSO dimethyl sulfoxideTEA triethylamine HCl hydrochloric acid H₂O water AcOH acetic acid MeOHmethanol EtOH ethanol Na₂CO₃ sodium carbonate NaOH sodium hydroxideSOCl₂ thionyl chloride TFA trifluoroacetic acid THF tetrahydrofuranMe³O⁺ BF₄ ⁻ trimethyloxonium tetrafluoroborate BF₃E_(t2)O borontrifluoride etherate PdCl₂(PPh₃)₂bis(triphenylphosphine)dichloropalladium Pd/C Palladium on carbon

Preparation of Intermediate Compound Intermediate Preparation Example 1:preparation of (1R,2R,5S)-ethyl4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (Compound 5) and(1R,2S,5S)-ethyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate(Compound 5′)

Step 1:

Compound 1 (14.3 g, 0.1 mol) was dissolved in dichloromethane (150 mL).The starting material, trimethyloxonium tetrafluoroborate (16.3 g, 0.11mol), was added in portions, and the reaction solution was reacted atroom temperature for 16 hours. The reaction solution was cooled in anice-water bath, adjusted to pH 8.0 with saturated sodium bicarbonatesolution, and extracted with dichloromethane (200 mL×2). The combinedorganic phase was dried with anhydrous sodium sulfate (100 g) for 30min, and then filtered and concentrated under reduced pressure. Theresulting crude product was separated and purified by columnchromatography (dichloromethane:methanol=9:1) to obtain Compound 2 (8.5g, a yellow oily matter, yield: 54%).

MS m/z (ESI): 158.0 [M+H]⁺.

Step 2:

A mixture of Compound 2 (8.5 g, 0.054 mol) and Compound 3 (21.6 g, 0.162mmol) was reacted at 60° C. for 16 horns. LC-MS indicated that thereaction of the starting materials was complete. To the reactionsolution, 50 g of silica gel was added, and it was separated andpurified by column chromatography (petroleum ether:ethyl acetate=3:2) toobtain Compound 4 (4 g, a yellow oily matter, yield: 29%).

¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (brs, 1H), 4.64 (dd, J=3.6 Hz, J=8.8Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.72 (s, 3H), 3.20-2.90 (m, 2H),2.50-2.30 (m, 1H), 2.10-2.00 (m, 1H), 1.23 (t, J=6.8 Hz, 3H).

MS m/z (ESI): 259.0 [M+H]⁺.

Step 3:

Compound 4 (12 g, 46.47 mmol) was dissolved in ethanol (1.2 L), and 12 g10% wet palladium on carbon was added. The reaction solution was purgedwith hydrogen 5 times in an enclosed tank, and then reacted under thehydrogen atmosphere (0.4 MPa) at room temperature for 72 hours. Aftercompleting reaction, it was filtered, and concentrated. The resultingcrude product was separated and purified by column chromatography(dichloromethane:methanol=10:1) to obtain two isomers: Compound 5 (3 g,a yellow solid, yield: 32.6%) and Compound 5′ (1.5 g, a brown yellowsolid, 16.3%).

Compound 5:

¹H NMR (400 MHz, DMSO-d₆): δ 7.25 (s, 1H), 4.25 (d, J=4.4 Hz, 1H),4.20-4.10 (m, 2H), 3.75-3.7 (m, 1H), 3.39 (d, J=6.4 Hz, 1H), 1.80-1.60(m, 3H), 1.50-1.40 (m, 1H), 1.21 (t, J=9.2 Hz, 3H).

MS m/z (ESI): 199.0 [M+H]⁺.

Compound 5′:

¹H NMR (400 MHz, DMSO-d₆): δ 7.38 (s, 1H), 4.20-4.05 (m, 2H), 3.84 (d,J=6.8 Hz, 1H), 3.68 (s, 1H), 3.42 (d, J=6.0 Hz, 1H), 1.95-1.65 (m, 4H),1.20 (t, J=6.4 Hz, 3H).

MS m/z (ESI): 199.0 [M+H]⁺.

The intermediate compounds in Table 1 were prepared by methods similarto that described in the Intermediate Preparation Example 1.

TABLE 1 Starting material or reaction condition different from that inIntermediate Preparation Compound Structure Compound Name Example 1Characterization data

5* (1S,2R,5R)-ethyl 4-oxo-3,8-diazabicyclo [3.2.1]octane-2- carboxylate;Compound 1 in step 1 of Intermediate Preparation Example 1 was replacedwith

¹H NMR (400 MHz, DMSO-d₆): δ 7.38 (s, 1H), 4.20-4.05 (m, 2H), 3.84 (d, J= 6.8 Hz, 1H), 3.68 (s, 1H), 3.42 (d, J = 6.0 Hz, 1H), 1.95-1.65 (m,4H), 1.20 (t, J = 6.4 Hz, 3H). MS m/z (ESI): 199.0 [M + H]⁺.

5^(#) (1S,2S,5R)-ethyl 4-oxo-3,8-diazabicyclo [3.2.1]octane-2-carboxylate Compound 1 in step 1 of Intermediate Preparation Example 1was replaced with

¹H NMR (400 MHz, DMSO-d₆): δ 7.25 (s, 1H), 4.25 (d, J = 4.4 Hz, 1H),4.20-4.10 (m, 2H), 3.75-3.70 (m, 1H), 3.39 (d, J = 6.4 Hz, 1H),1.80-1.60 (m, 3H), 1.50-1.40 (m, 1 H), 1.21 (t, J = 9.2 Hz, 3H). MS m/z(ESI): 199.0 [M + H]⁺.

Intermediate Preparation Example 2: preparation of (1R,2R,5S)-ethyl3,8-diazabicyclo[3.2.1]octane-2-carboxylate (Compound 6)

Compound 5 (3 g, 15.13 mmol) obtained from Intermediate PreparationExample 1 was dissolved in a solution of borane dimethylsulfide intetrahydrofuran (2M, 20 mL), purged with nitrogen for 5 times, andreacted at room temperature in a nitrogen atmosphere for 16 horns. Afterthe reaction was complete, the reaction solution was slowly poured intomethanol and stirred at 50° C. for 16 hours, and then the reaction wasquenched. The resulting crude product was separated and purified bycolumn chromatography (dichloromethane:methanol=20:1) to obtain Compound6 (1.5 g, a brown yellow oily matter, yield: 54%).

¹H NMR (400 MHz, DMSO-d₆): δ 6.42 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.78(s, 1H), 3.30 (d, J=5.2 Hz, 1H), 3.13 (d, J=6.4 Hz, 1H), 2.90 (d, J=12.4Hz, 1H), 2.70-2.50 (m, 2H), 2.05-1.85 (m, 2H), 1.80-1.60 (m, 1H),1.50-1.40 (m, 1H), 1.19 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 185.0 [M+H]⁺.

The intermediates in Table 2 were prepared by methods similar to thatdescribed in the Intermediate Preparation Example 2.

TABLE 2 Starting material or reaction condition different from that inIntermediate Compound Structure Compound Name Preparation Example 2Characterization data

6* (1S,2R,5R)-ethyl 3,8-diazabicyclo[3.2.1] octane-2-carboxylateCompound 5 of Intermediate Preparation Example 2 was replaced withCompound 5*. ¹H NMR (400 MHz, DMSO-d₆): δ 5.65 (s, 1H), 4.10 (q, J = 9.6Hz, 2H), 3.50 (d, J = 7.2 Hz, 1H), 3.34 (s, 1H), 3.28 (s, 1H), 3.11 (d,J = 8.4 Hz, 1H) , 2.99 (d, J = 16.4 Hz, 1H), 2.22-1.60 (m, 4H), 1.19 (t,J = 9.2 Hz, 3H). MS m/z (ESI): 185.0 [M + H]⁺.

6^(#) (1S,2S,5R)-ethyl 3,8-diazabicyclo[3.2.1] octane-2-carboxylateCompound 5 of Intermediate Preparation Example 2 was replaced withcompound 5^(#). ¹H NMR (400 MHz, DMSO-d₆): δ 6.42 (s, 1H), 4.10 (q, J =7.2 Hz, 2H), 3.78 (s, 1H), 3.30 (d, J = 5.2 Hz, 1H), 3.13 (d, J = 6.4Hz, 1H), 2.90 (d, J = 12.4 Hz, 1H), 2.70-2.50 (m, 2H), 2.05- 1.85 (m,2H), 1.80-1.60 (m, 1H), 1.50-1.40 (m, 1 H), 1.19 (t, J = 7.2 Hz, 3H). MSm/z (ESI): 185.0 [M + H]⁺.

Intermediate Preparation Example 3: preparation of (1R,2S,5S)-ethyl3,8-diazabicyclo[3.2.1]octane-2-carboxylate (Compound 6′)

By a method similar to Intermediate Preparation Example 2, Compound 6′(0.16 g, a brown yellow oily liquid, 11%) was obtained from Compound 5′(1.5 g, 7.57 mmol) obtained in Intermediate Preparation Example 1.

¹H NMR (400 MHz, DMSO-d₆): δ 5.65 (s, 1H), 4.10 (q, J=9.6 Hz, 2H), 3.50(d, J=7.2 Hz, 1H), 3.34 (s, 1H), 3.28 (s, 1H), 3.11 (d, J=8.4 Hz, 1H),2.99 (d, J=16.4 Hz, 1H), 2.22-1.60 (m, 4H), 1.19 (t, J=9.2 Hz, 3H).

MS m/z (ESI): 185.0 [M+H]⁺.

Preparation of compounds of the invention Example 1: preparation of(1R,2S,5S)-3,8-bis(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C1)

Step 1:

Compound 6 (0.15 g, 0.81 mmol) obtained from Intermediate PreparationExample 2 was dissolved in dichloromethane (30 mL). triethylamine (0.267g, 2.64 mmol) and Compound 7 (0.203 g, 0.81 mmol) were added and reactedat room temperature for 4 hours. LC-MS indicated that the reaction ofthe starting materials was complete. The solution was then quenched byadding water (30 mL), and extracted with ethyl acetate (20 mL/3). Thecombined organic phases were washed with saturated brine (50 mL×3).After that, the organic phases were dried by adding anhydrous sodiumsulfate for 30 min, and then filtered. The filtrate was concentratedunder reduced pressure. The resulting crude product was subjected toseparation by column chromatography (petroleum ether:methyl tert-butylether=3:7) to obtain Compound C1-1 (50 mg, a dark yellow solid, yield:11%).

MS m/z (ESI): 573.0 [M+H]⁺.

Step 2:

Compound C1-1 (50 mg, 0.087 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL). Sodium hydroxide(35 mg, 0.87 mmol) was added and stirred at room temperature for 3horns. After concentrated, a crude product was obtained. The crudeproduct was adjusted to pH 5.0 with 3N hydrochloric acid solution, andthen extracted with ethyl acetate (20 mL×3). The combined organic phaseswere washed with saturated brine (50 mL×3). After that, the organicphases were dried by adding anhydrous sodium sulfate for 30 min and thenfiltered. The filtrate was concentrated under reduced pressure, and thecrude product was subjected to separation by reversed phasechromatography (acetonitrile/water (0.1% trifluoroacetic acid solution)60/40-70/30) to obtain the target compound C1 (15 mg, a light yellowsolid, yield: 31%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.50-7.00 (m, 20H), 5.50-5.30 (m, 2H), 5.02(s, 1H), 4.90-4.60 (m, 2H), 3.90-3.40 (m, 2H), 1.70-1.00 (m, 4H).

MS m/z (ESI): 545.0 [M+H]⁺.

The compounds in Table 3 were prepared by methods similar to thatdescribed in Example 1.

TABLE 3 Starting material or reaction condition different from that inNo. Compound Structure Compound Name Example 1 Characterization data C3

(1R,2S,5S)-3,8-bis (2,2-diphenylacetyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6′. ¹H NMR (400 MHz, DMSO-d₆): δ 7.35-7.00 (m, 20H), 5.49 (s, 1H), 5.37 (s, 1H), 5.14 (s, 1H), 4.73 (s, 1H), 4.57 (s,1H), 3.75-3.45 (m, 2H), 2.25-2.00 (m, 1H), 1.95-1.50 (m, 3H). MS m/z(ESI): 544.9 [M + H]⁺. C5

(1R,2S,5S)-3,8-bis (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 7 in step 1 of Example 1 wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 7.40-7.30 (m, 8H), 7.25-7.15 (m, 4H), 7.10-7.00 (m, 8H), 4.44 (s, 2H), 4.11 (s, 1H), 3.25-3.05 (m, 2H), 1.85-1.60(m, 2H), 1.55- 1.45 (m, 1H), 1.35-1.30 (m, 1H). MS m/z (ESI): 547.0 [M +H]⁺. C4

(1S,2R,5R)-3,8-bis (2,2-diphenylacetyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6^(#). ¹H NMR (400 MHz, CD₃OD): δ 7.57-7.03 (m,20H), 5.50 (d, J = 6.5 Hz, 1H), 5.35 (d, J = 8.5 Hz, 1H), 4.67 (s, 1H),4.33 (d, J = 20.2 Hz, 1H), 3.86 (d, J = 14.7 Hz, 1H), 3.65 (d, J = 21.2Hz, 1H), 3.48 (d, J = 13.3 Hz, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.11 (m,1H). MS m/z (ESI): 544.9 [M + H]⁺. C14

(1S,2R,5R)-3,8-bis (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6^(#), and Compound 7 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 13.19 (s, 1H), 7.33 (dd, J = 15.9, 8.1 Hz,8H), 7.16 (t, J = 7.3 Hz, 4H), 7.09-6.86 (m, 8H), 4.27 (m, 2H), 3.96 (m,1H), 3.16 (d, J = 13.5 Hz, 1H), 2.99-2.87 (m, 1H), 1.64 (m, 1H), 1.53(m, 1H), 1.29 (d, J = 37.9 Hz, 1H), 1.14 (m, 1H). MS m/z (ESI): 546.8[M + H]⁺. C8

(1R,2S,5S)-3,8-bis (5H-dibenzo[b,f] azepine-5-carbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7 in step 1of Example 1 was replaced with  

  and reacted at 50° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.76 (s, 1H),7.56-6.99 (m, 20H), 4.38 (m, 1H), 3.92 (s, 1H), 3.18 (s, 1H), 2.02 (m,1H), 1.46 (s, 1H), 1.24 (s, 2H), 1.12-0.96 (m, 2H). MS m/z (ESI): 595.0[M + H]⁺. C41

(1R,2S,5S)-3,8-bis (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6′, and Compound 7 was replaced with  

¹H NMR (400 MHz, CD₃OD): δ 7.40-7.30 (m, 8H), 7.25-7.15 (m, 4H), 7.10-7.00 (m, 8H), 4.48 (s, 2H), 4.1 (s, 1H), 3.30-3.10 (m, 2H), 1.85-1.40(m, 4H). MS m/z (ESI): 547.0 [M + H]⁺. and reacted at 50° C. C2

(1S,2R,5R)-3,8-bis (2,2-diphenylacetyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6* and reacted at room temperature for 16 hours.The reaction time in step 2 was 16 hours, and the condition of thereverse phase ¹H NMR (400 MHz, DMSO-d₆): δ 7.41-7.03 (m, 20H), 5.46 (dd,J = 29.9, 16.6 Hz, 2H), 5.16 (dd, J = 97.5, 9.8 Hz, 1H), 4.75-4.64 (m,1H), 4.56 (s, 1H), 4.39 (s, 1H), 3.22-3.11 (m, 1H), 1.39 (d, J = 6.7 Hz,2H), 1.07 (s, 1H), 0.87 (t, J = 7.3 Hz, 1H). MS m/z (ESI): 544.8 [M +H]⁺. chromatography was acetonitrile/water = 55/75. C13

(1S,2R,5R)-3,8-bis (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 6 in step 1 of Example 1 wasreplaced with compound 6*, and Compound 7 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 13.23 (s, 1H), 7.32 (dd, J = 15.8 Hz, J =8.0 Hz, 8H), 7.15 (t, J = 7.2 Hz, 4H), 7.05-6.89 (m, 8H), 4.27 (s, 2H),3.96 (s, 1H), 3.15 (d, J = 12.8 Hz, 1H), 2.96 (s, 1H), 1.64 (s, 1H),1.51 (s, 1H), 1.29 (d, J = 40.5 Hz, 2H). MS m/z (ESI): 546.8 [M + H]⁺.and reacted at 45° C. for 48 hours. The reaction time in step 2 was 16hours, and the condition of the reverse phase chromatography wasacetonitrile/water = 50/80.

Example 2: preparation of(1R,2S,5S)-3-benzoyl-8-(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C31)

Step 1:

Compound 6 (2.3 g, 12.48 mmol) obtained from Intermediate PreparationExample 2 was dissolved in a dichloromethane solution (50 mL), cooledwith an ice-water bath, followed by sequential addition of di-tert-butyldicarbonate (2.7 g, 12.48 mmol) and triethylamine (3.78 g, 37.45 mmol)and reaction at room temperature for 16 hours. After the reaction wascomplete, 50 mL water was added to the reaction solution and extractedwith dichloromethane (50 mL×2). The combined organic phases were driedover anhydrous sodium sulfate (100 g) for 30 min and then filtered. Thefiltrate was concentrated under reduced pressure. The resulting crudeproduct was separated and purified by column chromatography (petroleumether:ethyl acetate=3:7) to obtain Compound 8 (1.4 g, a yellow oilymatter, crude product).

¹H NMR (400 MHz, DMSO-d₆): δ 6.80 (s, 1H), 4.20-4.00 (m, 3H), 3.45-3.40(m, 2H), 3.30-3.20 (m, 2H), 2.20-2.10 (m, 1H), 2.00-1.85 (m, 2H),1.65-1.55 (m, 1H), 1.38 (s, 9H), 1.20 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 307.0 [M+Na]+.

Step 2:

Compound 8 (1.4 g, 4.92 mmol) was dissolved in dichloromethane (20 mL).To the resulting solution, triethylamine (1.49 g, 14.77 mmol) and then asolution of Compound 7 (1.14 g, 4.92 mmol) in dichloromethane (10 mL)were added. After reacting at room temperature for 3 hours, LC-MSindicated that the reaction of the starting materials was complete. Thesolution was quenched by adding water (30 mL) and extracted withdichloromethane (20 mL×3). The combined organic phases were washed withsaturated brine (50 mL×3). After that, the organic phases were dried byadding anhydrous sodium sulfate for 30 min, and then filtered andconcentrated under reduced pressure. The resulting crude product wassubjected to separation by column chromatography (petroleum ether:methyltert-butyl ether=3:2) to obtain Compound 9 (0.8 g, a dark yellow solid,crude product).

MS m/z (ESI): 479.0 [M+H]⁺.

Step 3:

Compound 9 (0.8 g, 1.67 mmol) was dissolved in a hydrochloric acidsolution in ethanol (8M, 10 mL), and reacted at room temperature for 2hours. After the reaction was complete, a crude product of compound 10was obtained by concentration (0.5 g, a dark yellow solid, crudeproduct).

MS m/z (ESI): 379.0 [M+H]⁺.

Step 4:

Compound 10 (0.25 g, 0.6 mmol) was dissolved in dichloromethane (20 mL),followed by sequential addition of Compound 11 (85 mg, 0.6 mmol) andtriethylamine (0.183 g, 1.8 mmol) and reaction at room temperature for16 horns. After the reaction was complete, 50 mL water was added to thereaction solution and extracted with dichloromethane (50 mL×2). Thecombined organic phases were dried with anhydrous sodium sulfate (100 g)for 30 min, then filtered and concentrated under reduced pressure. Theresulting crude product was separated and purified by columnchromatography (petroleum ether:ethyl acetate=3:2) to obtain CompoundC31-1 (0.2 g, a yellow oily matter, 69%).

MS m/z (ESI): 483.0 [M+H]⁺.

Step 5:

Compound C31-1 (0.2 g, 0.41 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL), followed by addingsodium hydroxide (83 mg, 2.07 mmol) and stirring at room temperature for3 horns. After concentration, the obtained crude product was adjusted topH 5.0 with 3N hydrochloric acid solution. A solid was filtered andwashed with 10 mL water, and then dried to obtain Compound C31 (130 mg,a light yellow solid, yield: 70%)

¹H NMR (400 MHz, DMSO-d₆): δ 7.50-7.00 (m, 15H), 5.50-5.30 (m, 1H),5.20-4.90 (m, 1H), 4.70-4.40 (m, 2H), 4.25-3.80 (m, 1H), 3.25-3.00 (m,1H), 1.8-1.25 (m, 4H).

MS m/z (ESI): 455.0 [M+H]⁺.

The compounds in Table 4 were prepared by methods similar to thatdescribed in Example 2.

TABLE 4 Starting material or reaction condition Compound Compounddifferent from that in No. Structure Name Example 2 Characterizationdata C7

(1R,2S,5S)-3-(5H- dibenzo[b,f] azepine-5- carbonyl)-8-(diphenylcarbamoyl)- 3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acidCompound 7 in step 2 of Example 2 was replaced with  

  Compound 11 in step 4 of Example ¹H NMR (400 MHz, CD₃OD): δ 7.70-6.90(m, 20H), 4.32 (s, 1H), 4.20 (s, 1H), 3.98 (d, J = 5.6 Hz, 1H), 2.93 (s,2H), 1.80- 1.50 (m, 2H), 1.425-1.40 (m, 2H). MS m/z (ESI): 571.0 [M +H]⁺. 2 was replaced with

And the reactions in step 2 and step 4 were performed at 50° C. C6

(1R,2S,5S)-8-(5H- dibenzo[b,f] azepine-5-carbonyl)- 3-(diphenylcarbamoyl)- 3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acidCompound 7 in step 2 of Example 2 was replaced with  

  Compound ¹H NMR (400 MHz, CD₃OD): δ 7.59-6.96 (m, 20H), 4.90 (s, 1H),4.41 (s, 1H), 3.50-3.33 (m, 1H), 3.15 (s , 1H), 2.88 (d, J = 12.8 Hz,1H), 2.37 (s, 2H), 2.00-1.96 (m, 2H), 1.70-1.31 (m, 3H). MS m/z (ESI):571.0 [M + H]⁺. 11 in step 4 of the Example was replaced with

And, the reactions in step 2 and step 4 were performed at 50° C. C9

(1R,2S,5S)-8-(5H- dibenzo[b,f] azepine-5- carbonyl)-3-(2,2-diphenylacetyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 7 in step 2 of Example 2 was replaced with  

  Compound ¹H NMR (400 MHz, CD₃OD): δ 7.27-6.96 (m, 20H), 5.19 (d, J =20.0 Hz, 1H), 4.90-4.77 (m, 2H), 4.40 (s, 1H), 3.53 (d, J = 16 Hz, 1H),3.41 (d, J = 4.0 Hz, 1H), 3.18 (d, J = 12.0 Hz, 1H), 2.60 (d, J = 12.0Hz, 1H), 2.20 (d, J = 12.0 Hz, 1H), 1.84-1.81 (m, 1H), 1.49-1.31 (m,2H). MS m/z (ESI): 570.0 [M + H]⁺. 11 in step 4 was replaced withCompound 7. C10

(1R,2S,5S)-3-(5H- dibenzo[b,f] azepine-5-carbonyl)- 8-(2,2-diphenylacetyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 11 in step 4 of Example 2 was replaced with  

  and the ¹H NMR (400 MHz, DMSO-d₆): δ 7.70-6.90 (m, 20H), 5.34-5.21 (m,1H), 4.83- 4.43 (m, 1H), 4.23-4.16 (m, 1H), 3.97-3.31 (m, 1H), 3.10-2.70(m, 2H), 1.60-0.80 (m, 4H). MS m/z (ESI): 570.0 [M + H]⁺. reaction instep 4 was performed at 50° C. C12

(1R,2S,5S)-8-(2,2- diphenylacetyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 11 in step 4of Example 2 was replaced with  

  and the ¹H NMR (400 MHz, CD₃OD) δ 7.50-7.00 (m, 20H), 5.49- 5.34 (m,1H), 5.14-4.67 (m, 2H), 4.37 (s, 1H), 3.65-3.35 (m, 2H), 1.60-0.80 (m,4H). MS m/z (ESI): 546.0 [M + H]⁺. reaction in step 4 was performed at50° C. C28

(1R,2S,5S)-8-(2,2- diphenylacetyl)- 3-(10H- phenothiazine-10-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound 11in step 4 of Example 2 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 7.60-7.00 (m, 18H), 5.39-5.28 (s, 1H), 4.97(s, 1H), 4.60 (s, 1H), 4.39 (s, 1H), 3.20-2.80 (m, 2H), 1.70- 1.10 (m,4H). MS m/z (ESI): 575.9 [M + H]⁺. C63

(1R,2S,5S)-8-(2,2- diphenylacetyl)- 3-(pyrrolidine- 1-carbonyl)-3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound 11 in step 4of Example 2 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 7.50-6.90 (m, 10H), 5.52-5.43 (m, 1H),5.10- 4.20 (m, 3H), 3.50-3.10 (m, 6H), 1.78 (m, 4H), 1.75-1.00 (m, 4H).MS m/z (ESI): 448.0 [M + H]⁺. C68

(1R,2S,5S)-8-(2,2- diphenylacetyl)-3- (phenoxycarbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 11 in step 4of Example 2 was replaced with phenyl chloroformate. ¹H NMR (400 MHz,DMSO-d₆): δ 7.70-6.90 (m, 15H), 5.50-5.30 (m, 1H), 5.10- 4.50 (m, 3H),4.00-3.00 (m, 2H), 1.90-1.50 (m, 4H). MS m/z (ESI): 570.9 [M + H]⁺. C70

(1R,2S,5S)-8-(2,2- diphenylacetyl)-3-(3- phenylpropionyl)-3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acid Compound 11 in step 4of Example 2 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 7.50-6.90 (m, 15H), 5.50-5.20 (m, 1H),5.10- 4.50 (m, 4H), 3.60-3.20 (m, 2H), 2.80-2.50 (m, 3H), 1.80- 1.20 (m,4H). MS m/z (ESI): 483.0 [M + H]⁺. C71

(1S,2R,5R)-3- (5H-dibenzo[bf] azepine-5-carbonyl)- 8-(2,2-diphenylacetyl)-3,8- diazabicyclo[3. 2.1]octane-2- carboxylic acidCompound 6 in step 1 of Example 2 was replaced with compound 6^(#). Thereaction time in step 2 was 16 hours. In step 4, Compound 11 wasreplaced with  

¹H NMR (300 MHz, CD₃OD): δ 7.60-6.94 (m, 20H), 5.31 (d, J = 42.0 Hz,1H), 4.99 (s, 1H), 4.62-4.50 (m, 1H), 4.30 (d, J = 37.8 Hz, 1H),3.16-2.85 (m, 2H), 1.71-0.93 (m, 4H). MS m/z (ESI): 569.8 [M + H]⁺. thereaction temperature was 50° C. and the reaction time was 48 hours. Thereaction time in step 5 was 16 hours. C72

(1S,2R,5R)-8- (5H-dibenzo[bf] azepine-5-carbonyl)- 3-(2,2-diphenylacetyl)-3,8- diazabicyclo[3. 2.1]octane-2- carboxylic acidCompound 6 in step 1 of Example 2 was replaced with compound 6^(#). Instep 2, Compound 7 was replaced with  

¹H NMR (400 MHz, CD₃OD): δ 7.61 (d, J = 8.3 Hz, 1H), 7.47- 6.90 (m,19H), 5.22 (d, J = 7.9 Hz, 1H), 4.80 (d, J = 7.4 Hz, 1H), 3.57 (d, J =11.3 Hz, 1H), 3.51-3.43 (m, 1H), 3.25-3.12 (m, 1H), 2.53 (d, J = 11.1Hz, 1H), 1.88-1.77 (m, 1H), 1.52- 1.34 (m, 2H), 0.99 (d, J = 9.2 Hz,1H). MS m/z (ESI): 569.9 [M + H]⁺. the reaction time was 48 hours andthe reaction temperature was 40° C. Compound 11 in step 4 was replacedwith compound 7. The reaction time in step 5 was 16 hours, and thereaction temperature was 50° C. C73

(1R,2S,5S)-3- ((benzyloxy) carbonyl)-8-(5H- dibenzo[bf]azepine-5-carbonyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acid In step2, Compound 7 of Example 2 was replaced with  

  the reaction time was 48 hours, and the reaction temperature ¹H NMR(300 MHz, CD₃OD) δ 7.70-7.18 (m, 13H), 7.01 (s, 2H), 5.21-4.99 (m, 2H),4.77 (s, 1H), 4.44 (s, 1H), 4.20-3.76 (m, 1H), 3.59 (s, 1H), 3.21-3.04(m, 1H), 2.35 (dd, J = 22.2, 11.7 Hz, 1H), 1.85 (s, 1H), 1.59 (s, 3H),1.28 (s, 1H). MS m/z (ESI): 510.0 [M + H]⁺. was 40° C. Compound 11 instep 4 was replaced with benzyl chloroformate. C77

(1S,2R,5R)-3- ((benzyloxy) carbonyl)- 8-(5H-dibenzo [b,f]azepine-5-carbonyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound6 in step 1 of Example 2 was replaced with compound 6^(#). In step 2, 4-Dimethylaminopyridine was added and Compound 7 was replaced with  

¹H NMR (400 MHz, DMSO-d₆): δ 13.04 (s, 1H), 7.66-7.00 (m, 15H), 5.01(dt, J = 12.9 Hz, J = 10.9 Hz, 2H), 4.63 (t, J = 7.7 Hz, 1H), 4.34 (dd,J = 17.1, J = 2.5 Hz, 1H), 3.48 (s, 1H), 3.06 (dd, J = 25.2, J = 9.8 Hz,1H), 2.18 (dd, J = 47.4 Hz, J = 10.4 Hz, 1H), 1.73 (s, 1H), 1.64-1.36(m, 3H). MS m/z (ESI): 509.9 [M + H]⁺. and the reaction time was 48hours and the reaction temperature was 40° C. In step 4, Compound 11 wasreplaced with benzyl chloroformate, and the reaction tempearture was 45°C. The reaction time in step 5 was 16 hours, and the reactiontemperature was 45° C. C75

(1S,2R,5R)-3- ((benzyloxy) carbonyl)-8-(2,2- diphenylacetyl)-3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acid Compound 6 in step 1 ofExample 2 was replaced with compound 6^(#). The reaction time in step 2was 16 hours. In step 4, Compound 11 was replaced with benzylchloroformate, 4- dimethylaminopyridine was added, and the reactiontemperature was 40° C., and the reaction time was 48 hours. The reactiontime in step 5 was 16 hours. ¹H NMR (400 MHz, DMSO-d₆): δ 13.30 (dd, J =286.6, 29.9 Hz, 1H), 7.50-7.03 (m, 15H), 5.50-5.26 (m, 1H), 5.19-4.98(m, 2H), 4.78-4.63 (m, 1H), 4.52 (t, J = 27.1 Hz, 1H), 4.35 (dd, J =23.9 Hz, J = 1.9 Hz, 1H), 3.80-3.45 (m, 1H), 3.22-2.93 (m, 1H), 1.83-1.43 (m, 4H). MS m/z (ESI): 484.9 [M + H]⁺. C20

(1R,2S,5S)-8-(5H- dibenzo[b,f] azepine-5-carbonyl)- 3-(diphenylcarbamoyl)- 3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acidIn step 2 of Example 2, 4- dimethylaminopyridine was added, Compound 7was replaced with  

  and the ¹H NMR (400 MHz, CD₃OD): δ 7.64 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 3H), 7.35-7.29 (m, 3H), 7.09-7.02 (m, 2H), 4.84 (s, 1H), 4.48(s, 1H), 3.52 (s, 2H), 3.15-3.03 (s, 2H), 3.01- 2.78 (m, 4H), 2.69-2.64(m, 2H), 1.88-1.84 (m, 1H), 1.80- 1.66 (m, 1H), 1.66-1.57 (m, 2H),1.56-1.44 (m, 3H), 1.40- 1.29 (m, 3H), 1.27-1.15 (m, 2H), 0.94-0.86 (m,6H), 0.82- 0.78 (m, 2H). MS m/z (ESI): 559.1 [M + H]⁺. reaction time was48 hours and the reaction temperature was 40° C. Compound 11 in step 4was replaced with Di-pentyl amine. C45

(1R,2S,5S)-3-(10, 11-dihydro-5H- dibenzo[bf]azepine- 5-carbonyl)-8-(diphenylcarbamoyl)- 3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acidCompound 7 in step 2 of Example 2 was replaced with  

  Compound 11 in step 4 was ¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J = 5.6Hz, 2H), 7.32 (d, J = 7.6 Hz, 4H), 7.24-7.15 (m, 8H), 7.06 (d, J = 7.6Hz, 4H), 4.42-4.30 (m, 3H), 4.12- 4.05 (m, 1H), 3.25-3.05 (m, 6H),1.80-1.30 (m, 4H). MS m/z (ESI): 572.8 [M + H]⁺. replaced with

C69

(1R,2S,5S)-8- (diphenylcarbamoyl)- 3- (phenoxycarbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7 in step 2Example 2 was replaced with  

  Compound ¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.31 (m, 6H), 7.25-7.15 (m,3H), 7.12-7.01 (m, 6H), 4.60- 4.35 (m, 2H), 4.17-4.10 (m, 1H), 3.60-3.50(m, 2H), 1.90- 1.60 (m, 4H). MS m/z (ESI): 472.1 [M + H]⁺. 11 in step 4was replaced with phenyl chloroformate.

Example 3: Preparation of(1S,2R,5R)-8-((benzyloxy)carbonyl)-3-(5H-dibenzo[b,f]azepine-5-carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C81)

Step 1:

Compound 6^(#) (36.8 mg, 0.2 mmol) was dissolved in dichloromethane (20mL), and Compound 13 (51.2 mg, 0.2 mmol) and triethylamine (60.6 mg, 0.6mmol) were then added sequentially. The mixture was reacted in a sealedtube at 50° C. for 16 hours. After the reaction was complete, 20 mLwater was added to the reaction solution and extracted withdichloromethane (20 mL×3). The combined organic phases were washed withsaturated brine (20 mL×2) and dried by adding anhydrous sodium sulfatefor 30 min, then filtered and concentrated under reduced pressure toobtain a crude product. The resulting crude product was separated andpurified by column chromatography (petroleum ether:ethyl acetate=1:1) toobtain Compound 14 (40.3 mg, a yellow solid, 50%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.65-7.25 (m, 8H), 7.05 (d, J=7.5 Hz, 2H),4.15 (m, 2H), 4.03 (dd, J=14.2, 7.1 Hz, 2H), 3.76 (d, J=4.6 Hz, 1H),3.55 (d, J=6.3 Hz, 1H), 3.02 (dd, J=14.1, 6.8 Hz, 1H), 1.82 (m, 1H),1.60 (m, 1H), 1.53-1.34 (m, 2H), 1.24-1.14 (t, J=7.1 Hz, 3H). MS m/z(ESI): 404.0 [M+H]⁺.

Step 2:

Compound 14 (40.3 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL),and Compound 15 (51 mg, 0.3 mmol) and triethylamine (0.05 g, 0.5 mmol)was added sequentially. The reaction was carried out at 50° C. for 16horns. After the reaction was complete, 20 mL water was added to thereaction solution and extracted with dichloromethane (20 mL×2). Thecombined organic phases were dried with anhydrous sodium sulfate (50 g)for 30 min, then filtered and concentrated under reduced pressure. Theresulting crude product was separated and purified by columnchromatography (petroleum ether:ethyl acetate=10:1) to obtain CompoundC81-1 (25 mg, a yellow solid, 46%).

¹H NMR (400 MHz, CD₃OD): δ 7.55 (d, J=8.0 Hz, 1H), 7.49-7.39 (m, 4H),7.34 (ddd, J=14.1, 10.6, 4.3 Hz, 8H), 7.06 (d, J=1.6 Hz, 2H), 5.04 (s,2H), 4.12 (q, J=7.1 Hz, 2H), 3.91 (s, 1H), 3.86-3.76 (m, 1H), 3.37 (m,1H), 3.26 (s, 2H), 1.94-1.74 (m, 1H), 1.70-1.57 (m, 1H), 1.34 (dd,J=7.4, 2.6 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).

MS m/z (ESI): 538.0 [M+H]⁺.

Step 3:

Compound C81-1 (25 mg, 0.0466 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL), followed by addingsodium hydroxide (5.6 mg, 0.14 mmol) and stirring at room temperaturefor 16 hours. After concentration, the obtained crude product wasadjusted to pH 5.0 with 3N hydrochloric acid solution, and filtered. Theobtained solid was washed with 10 mL water, and then dried. The obtainedcrude product of the compound was subjected to separation by reversedphase chromatography (acetonitrile/water (0.1% trifluoroacetic acidsolution) 55/45-85/15) to obtain the target compound C81 (3.41 mg, awhite solid, yield: 14.4%).

¹H NMR (300 MHz, DMSO-d₆): δ 7.29 (dd, J=40.7, 31.1 Hz, 15H), 5.01 (dd,J=15.4, 9.5 Hz, 2H), 4.60 (s, 1H), 4.32 (d, J=11.5 Hz, 1H), 3.45 (s,1H), 3.08-2.92 (m, 2H), 1.57 (d, J=79.4 Hz, 3H), 1.22-1.17 (m, 1H).

MS m/z (ESI): 510.1 [M+H]⁺.

The compounds in Table 5 were prepared by methods similar to thatdescribed in Example 3.

TABLE 5 Starting material or reaction condition different from that inNo. Compound Structure Compound Name Example 3 Characterization data C80

(1R,2S,5S)-8- ((benzyloxy) carbonyl)-3-(5H- dibenzo[b,f] azepine-5-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound6^(#) in step 1 of Example 3 was replaced with compound 5. ¹H NMR (400MHz, DMSO-d₆) δ 7.59 (s, 2H), 7.47-7.24 (m, 10H), 7.05 (s, 2H),5.07-5.00 (m, 1H), 4.92 (s, 1H), 4.48 (d, J = 6.8 Hz, 1H), 4.06 (s, 1H),4.01 (d, J = 2.4 Hz, 1H), 3.15-2.97 (m, 2H), 1.75-1.62 (m, 1H), 1.60-1.47 (m, 1H), 1.33-1.20 (m, 1H), 1.15-1.05 (m, 1H). MS m/z (ESI): 510.2[M + H]⁺.

Example 4: preparation of(1R,2S,5S)-3-(benzyl(methyl)carbamoyl)-8-(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C62)

Step 1:

Compound 10 (0.1 g, 0.264 mmol) was dissolved in a dichloromethanesolution (15 mL), cooled to 0° C. with an ice-water bath. Triphosgene(118 mg, 0.396 mmol) and triethylamine (82 mg, 0.792 mmol) were added tothe solution and reacted at 0° C. for 2 hours. Compound 16 (48 mg, 0.396mmol) was then added to the reaction solution, and was slowly heated upto room temperature and reacted at room temperature for 16 horns. Afterthe reaction was complete, 50 mL water was added to the reactionsolution and extracted with dichloromethane (50 mL/2). The combinedorganic phases were then dried by adding anhydrous sodium sulfate (30 g)for 30 min, then filtered and concentrated under reduced pressure. Theresulting crude product was separated and purified by columnchromatography (petroleum ether:ethyl acetate=2:3) to obtain CompoundC62-1 (50 mg, a yellow oily matter, 36%).

MS m/z (ESI): 526 [M+H]⁺.

Step 2:

Compound C62-1 (50 mg, 0.095 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL), followed by addingsodium hydroxide (38 mg, 0.95 mmol) and stirring at room temperature for2 hours. After concentration, the obtained crude product was adjusted topH 5.0 with 3N hydrochloric acid solution, and extracted with ethylacetate (20 mL/3). The combined organic phases were washed withsaturated brine (20 mL×3). After that, the organic phases were dried byadding anhydrous sodium sulfate for 30 min, and then filtered. Thefiltrate was concentrated under reduced pressure. The resulting crudeproduct was subjected to separation by reversed phase preparativechromatography (acetonitrile/water (0.1% trifluoroacetic acid solution)25/75-50/50) to obtain Compound C₆₂ (12 mg, light yellow solid, yield:25%).

¹H NMR (400 MHz, CD₃OD): δ 7.50-6.90 (m, 15H), 5.58-5.40 (m, 1H),5.00-4.20 (m, 5H), 3.60-3.30 (m, 2H), 2.80-2.70 (m, 3H), 2.00-1.10 (m,4H).

MS m/z (ESI): 498.0 [M+H]⁺.

The compounds in Table 6 were prepared by methods similar to thatdescribed in Example 4.

TABLE 6 Starting material or reaction condition different from that inNo. Compound Structure Compound Name Example 4 Characterization data C64

(1R,2S,5S)-8-(2,2- diphenylacetyl)-3- (morpholine-4- carbonyl)-3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acid Compound 16 in step 1 ofExample 4 was replaced with morpholine. ¹H NMR (400 MHz, DMSO-d₆): δ7.50-7.00 (m, 10H), 5.43-4.84 (m, 1H), 5.00-4.20 (m, 3H), 3.60- 2.80 (m,10H), 2.00-1.10 (m, 4H). MS m/z (ESI): 464.1 [M + H]⁺. C19

(1R,2S,5S)-3- (dipentylcarbamoyl)- 8-(2,2- diphenylacetyl)-3,8-diazabicyclo[3.2.1] octane-2-carboxylic acid Compound 16 in step 1 ofExample 4 was replaced with Di-pentyl amine. ¹H NMR (400 MHz, CD₃OD): δ7.42-7.12 (m, 10H), 5.57-5.41 (m, 1H), 4.83 (s, 1H), 4.76-4.73 (m, 1H),4.58-4.46 (m, 1H), 3.62-3.49 (m, 3H), 3.31- 3.14 (m, 2H), 3.09-3.00 (m,2H), 2.79-2.72 (m, 1H), 1.96-1.89 (m, 1H), 1.80- 1.70 (m, 3H), 1.53-1.49(m, 4H), 1.43-1.23 (m, 8H), 0.96-0.90 (m, 8H). MS m/z (ESI): 534.1 [M +H]⁺. C61

(1R,2S,5S)-3- (benzylcarbamoyl)- 8-(2,2- diphenylacetyl)-3,8-diazabicyclo[3.2.1] octane-2- carboxylic acid Compound 16 in step 1 ofExample 4 was replaced with benzylamine. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.11 (m, 16H), 5.62 (s, 1H), 5.47 (d, J = 46.9 Hz, 1H), 4.83 (s,2H), 4.45-4.33 (m, 2H), 4.31-4.25 (m, 1H), 3.60 (s, 1H), 1.95-1.82 (m,1H), 1.79-1.62 (m, 2H), 1.38- 1.26 (m, 1H). MS m/z (ESI): 484.0 [M +H]⁺. C116

(1R,2S,5S)-3,8-bis (benzyl(methyl) carbamoyl)-3,8- diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 10 in step 1 of Example 4 wasreplaced with compound 6. The amout of compound 16 was increased from1.5 ¹H NMR (400 MHz, CD₃OD) δ 7.38-7.32 (m, 4H), 7.31- 7.23 (m, 6H),4.73-4.66 (m, 2H), 4.59 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 15.2 Hz, 1H),4.40 (d, J = 15.2 Hz, 1H), 4.29 (d, J = 15.2 Hz, times in Example 4 1H),4.06 (d, J = 6.0 Hz, 1H), to 2.5 times higher 3.77 (d, J = 10.4 Hz, 1H),3.49 than compound 6. (dd, J = 12.4, 2.0 Hz, 1H), 2.84 (s, 3H), 2.76 (s,3H), 2.10- 2.00 (m, 1H), 1.96-1.70 (m, 3H). MS m/z (ESI): 451.0 [M +H]⁺.

Example 5: preparation of(1R,2S,5S)-3-(2,2-diphenylacetyl)-8-(phenoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C79) and(1R,2S,5S)-8-(benzyl(methyl)carbamoyl)-3-(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C82)

Step 1:

Compound 5 (1.98 g, 10 mmol) was dissolved in a dichloromethane solution(40 mL) and cooled in an ice-water bath. Di-tert-butyl dicarbonate (2.18g, 10 mmol) and triethylamine (3.03 g, 30 mmol) were sequentially addedand reacted at room temperature for 16 hours. After the reaction wascomplete, 50 mL water was added to the reaction solution and extractedwith dichloromethane (50 mL/2). The combined organic phases were thendried by adding anhydrous sodium sulfate (100 g) for 30 min, thenfiltered and concentrated under reduced pressure. The resulting crudeproduct was separated and purified by column chromatography (petroleumether:ethyl acetate=1:1) to obtain Compound 17 (2.3 g, a yellow oilymatter, 77%).

¹H NMR (400 MHz, CD₃OD): δ 7.65 (brs, 1H), 4.50-4.40 (m, 2H), 4.25-4.15(m, 2H), 4.15-4.05 (m, 1H), 2.10-1.90 (m, 2H), 1.85-1.75 (m, 1H),1.60-1.50 (m, 1H), 1.42 (s, 9H), 1.23 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 321.0 [M+Na]+.

Step 2:

Compound 17 (2.3 g, 7.71 mmol) was dissolved in a solution of boranedimethylsulfide in tetrahydrofuran (2M, 20 mL), purged with nitrogen for5 times, and reacted at room temperature in a nitrogen atmosphere for 16horns. After the reaction was complete, the reaction was slowly quenchedwith methanol and stirred at 50° C. for 16 hours. A crude product ofcompound 18 was obtained by concentration, and was separated andpurified by column chromatography (petroleum ether:ethyl acetate=3:7) toobtain Compound 18 (1.1 g, a yellow oily matter, crude product).

¹H NMR (400 MHz, DMSO-d₆): δ 4.2-4.15 (m, 1H), 4.11 (q, J=7.2 Hz, 2H),3.93 (s, 1H), 3.52 (s, 1H), 2.80-2.55 (m, 2H), 1.80-1.55 (m, 4H), 1.42(s, 9H), 1.20 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 285.1 [M+Na]+.

Step 3:

Compound 18 (0.55 g, 1.934 mmol) was dissolved in dichloromethane (20mL). To the solution, Compound 7 (0.446 g, 1.934 mmol) and triethylamine(0.586 g, 5.80 mmol) was then added sequentially and reacted at roomtemperature for 48 hours. LC-MS indicated that the reaction of thestarting materials was complete. The solution was then quenched byadding water (30 mL), and extracted with dichloromethane (20 mL/3). Thecombined organic phases were washed with saturated brine (50 mL×3). Theorganic phases were dried by adding anhydrous sodium sulfate for 30 min,and then filtered. The filtrate was concentrated under reduced pressure.The resulting crude product was subjected to separation by columnchromatography (petroleum ether:methyl tert-butyl ether=2:3) to obtainCompound 19 (0.55 g, a dark yellow solid, crude product).

¹H NMR (400 MHz, CD₃OD): δ 7.35-7.10 (m, 10H), 5.43 (s, 1H), 4.20-4.00(m, 5H), 3.60-3.40 (m, 2H), 2.00-1.50 (m, 4H), 1.34 (s, 9H), 1.19 (t,J=7.2 Hz, 3H).

MS m/z (ESI): 479.0 [M+H]⁺.

Step 4:

Compound 19 (0.55 g, 1.15 mmol) was dissolved in a solution ofhydrochloric acid in ethanol (8M, 10 mL), and reacted at roomtemperature for 2 hours. After the reaction was complete, a crudeproduct of compound 20 was obtained by concentration (0.35 g, a yellowsolid, 81%).

MS m/z (ESI): 379.0 [M+H]⁺.

Step 5a:

Compound 20 (50 mg, 0.132 mmol) was dissolved in a dichloromethanesolution (20 mL). Phenyl chloroformate (42 mg, 0.264 mmol) andtriethylamine (0.133 g, 1.32 mmol) were added sequentially, and reactedat room temperature for 16 horns. After the reaction was complete, 50 mLwater was added to the reaction solution and extracted withdichloromethane (50 mL×2). The combined organic phases were dried withanhydrous sodium sulfate (100 g) for 30 min, then filtered andconcentrated under reduced pressure. The resulting crude product wasseparated and purified by column chromatography (petroleum ether:ethylacetate=3:2) to obtain Compound C79-1 (50 g, a yellow solid, 76%).

MS m/z (ESI): 499.0 [M+H]⁺.

Step 5b:

Compound 20 (50 mg, 0.132 mmol) was dissolved in dichloromethane (15mL), cooled to 0° C. in an ice-water bath. To the solution, triphosgene(59 mg, 0.198 mmol) and triethylamine (41 mg, 0.396 mmol) were added andreacted at 0° C. for 2 horns. Compound 16 (24 mg, 0.198 mmol) was thenadded to the reaction solution, and was slowly heated up to roomtemperature for further reaction at room temperature for 16 hours. Afterthe reaction was complete, 50 mL water was added to the reactionsolution and extracted with dichloromethane (50 mL/2). The combinedorganic phases were then dried by adding anhydrous sodium sulfate (30 g)for 30 min, then filtered and concentrated under reduced pressure. Theresulting crude product was separated and purified by columnchromatography (petroleum ether:ethyl acetate=2:3) to obtain CompoundC82-1 (50 mg, a yellow oily matter, 72%).

MS m/z (ESI): 526.0 [M+H]⁺.

Step 6:

Compound C79-1 (50 mg, 0.1 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL). Sodium hydroxide(40 mg, 1 mmol) was added, stirred at room temperature for 3 hours andthen concentrated. The obtained crude product was adjusted to pH 5.0with 3N hydrochloric acid solution, and extracted with ethyl acetate (20mL/3). The combined organic phases were washed with saturated brine (50mL×3). The organic phases were dried by adding anhydrous sodium sulfatefor 30 min, and then filtered The filtrate was concentrated underreduced pressure. The resulting crude product was subjected toseparation by reversed phase preparative chromatography(acetonitrile/water (0.1% trifluoroacetic acid solution) 40/60-20/80) toobtain Compound C79 (25 mg, a light yellow solid, yield: 53%).

¹H NMR (400 MHz, CD₃OD): δ 12.995 (brs, 1H), 7.50-6.90 (m, 15H),5.60-5.30 (m, 1H), 4.80-4.60 (m, 2H), 4.20-4.10 (m, 1H), 3.70-3.40 (m,2H), 2.10-1.40 (m, 4H).

MS m/z (ESI): 471.0 [M+H]⁺.

Compound C82-1 (50 mg, 0.095 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL). Sodium hydroxide(38 mg, 0.95 mmol) was added, stirred at room temperature for 2 hours,and then concentrated. The obtained crude product was adjusted to pH 5.0with 3N hydrochloric acid solution, and extracted with ethyl acetate (20mL/3). The combined organic phases were washed with saturated brine (20mL×3). The organic phases were dried by adding anhydrous sodium sulfatefor 30 min and then filtered. The filtrate was concentrated underreduced pressure. The resulting crude product was subjected toseparation by reversed phase preparative chromatography(acetonitrile/water (0.1% trifluoroacetic acid solution) 25/75-50/50) toobtain Compound C82 (30 mg, a light yellow solid, yield: 63%).

¹H NMR (400 MHz, CD₃OD): δ 7.50-6.90 (m, 15H), 5.46-5.38 (m, 1H),4.70-4.20 (m, 4H), 4.20-4.05 (m, 1H), 3.80-3.60 (m, 2H), 2.85-2.75 (m,3H), 2.05-1.45 (m, 4H).

MS m/z (ESI): 498.1 [M+H]⁺.

The compounds in Table 7 were prepared by methods similar to thatdescribed in Example 5,

TABLE 7 Starting material or Compound reagent different from No.Compound Structure Name that in Example 5 Characterization data C78

(1R,2S,5S)-8- (benzylcarbamoyl)- 3-(2,2- diphenylacetyl)-3,8-diazabicyclo[3. 2.1]octane-2- carboxylic acid Compound 16 in step 5bof Example 5 was replaced with benzylamine. The reaction in step 5a didnot take place. ¹H NMR (400 Hz, CD₃OD) δ 7.44-7.08 (m, 15H), 5.46 (s,1H), 5.23 (s, 1H), 4.52-4.49 (m, 1H), 4.45-4.21 (m, 3H), 4.17 (s, 1H),3.75 (s, 1H), 3.58- 3.55 (m, 1H), 2.23-2.19 (m, 1H), 2.05 (s, 1H),1.95-1.91 (m, 2H). MS m/z (ESI): 484.0 [M + H]⁺. C76

(1S,2R,5R)-8- ((benzyloxy) carbonyl)-3-(2,2- diphenylacetyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 5 in step 1of Example 5 was replaced with compound 5^(#). In step 5a, the phenylchloroformate was replaced with benzyl chloroformate; the reactiontemperature was 50° C. and the ¹H NMR (400 MHz, DMSO-d₆): δ 12.88 (s,1H), 7.43-7.07 (m, 15H), 5.51 (s, 1H), 5.14-4.90 (m, 3H), 4.69 (d, J =6.0 Hz, 2H), 4.20 (s, 1H), 3.73 (d, J = 11.2 Hz, 1H), 1.85 (s, 1H),1.70-1.52 (m, 2H), 1.12 (s, 1H). MS m/z (ESI): 485.1 [M + H]⁺. reactiontime was 48 hours. The reaction time in step 6 was 16 hours. Thereaction in step 5b did not take place. C157

(1R,2S,5S)-8- ((benzyloxy) carbonyl)-3-(2,2- diphenylacetyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7 in step 3of Example 5 was replaced with  

  The phenyl ¹H NMR (400 MHz, CD₃OD) δ 7.60-7.50 (m, 4H), 7.47-7.19 (m,11H), 5.11 (d, J = 12.4 Hz, 1H), 4.98 (d, J = 12.8 Hz, 1H), 4.84 (s,1H), 4.80 (d, J = 6.8 Hz, 1H), 3.85 (s, 1H), 3.40- 3.35 (m, 1H), 3.19(d, J = 12.4 Hz, 1H), 1.90-1.75 (m, 4H), 1.50-1.35 (m, 1H), 1.32-1.16(m, 2H). MS m/z (ESI): 498.8 [M + H]⁺. chloroformate in step 5a wasreplaced with benzyl chloroformate. The reaction in step 5b did not takeplace. C222

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (3- phenylpropionyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid The phenylchloroformate in step 5a of Example 5 was replaced with  

1H NMR (400 MHz, DMSO-d₆) δ 7.50-7.00 (m, 15H), 5.55-5.40 (m, 1H), 4.90-4.25 (m, 3H), 3.75-3.55 (m, 1H), 3.40-3.00 (m, 1H), 2.85- 2.40 (m, 4H),1.75-1.00 (m, 6H). MS m/z (ESI): 483.0 [M + H]⁺. and the reaction wasperformed at room temperature for 12 hours. The reaction in step 5b didnot take place. C223

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (3-phenylbutyryl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid The phenylchloroformate in step 5a of Example 5 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.00 (m, 15H), 5.55-5.40 (m, 1H), 4.87-4.25 (m, 3H), 3.75-3.60 (m, 1H), 3.30-3.00 (m, 2H), 2.75- 2.51 (m, 1H),2.49-2.25 (m, 1H), 1.75-1.00 (m, 7H). MS m/z (ESI): 497.1 [M + H]⁺. andthe reaction was performed at room temperature for 6 hours. The reactionin step 5b did not take place. C230

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (2-methyl-3- phenylpropionyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid The phenylchloroformate in step 5a of Example 5 was replaced with  

  and the reaction was performed at room temperature for ¹HNMR (400 MHz,DMSO-d6) δ 7.41-7.02 (m, 15H), 5.56- 5.40 (m, 1H), 4.96-4.78 (m, 1H),4.61 (d, J = 20.7 Hz, 1H), 4.50 (s, 1H), 4.42-4.28 (m, 1H), 4.25 (s,1H), 4.12-3.97 (m, 1H), 3.63 (dd, J = 26.0, 11.9 Hz, 1H), 3.03-2.86 (m,2H), 2.61 (s, 1H), 1.36 (s, 1H), 1.26-1.15 (m, 1H), 1.09-0.95 (m, 3H),0.92-0.85 (m, 1H), 0.80 (s, 1H). MS m/z (ESI): 496.8 [M + H]⁺. 6 hours.The reaction in step 5b did not take place. C231

(1R,2S,5S)-3-(2,2- diphenylacetyl)- 8-((E)-2-methyl-3- phenylacryloyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid The phenylchloroformate in step 5a of Example 5 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.00 (m, 15H), 6.54 (s, 1H), 5.55-5.30(m, 1H), 4.87-4.25 (m, 3H), 3.77 (d, J = 10.8 Hz, 1H), 3.50 (d, J = 10.8Hz, 1H), 1.93 (s, 3H), 1.75-1.00 (m, 4H). MS m/z (ESI): 495.0 [M + H]⁺.and the reaction was performed at room temperature for 6 hours. Thereaction in step 5b did not take place. C194

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (((4-methylbenzyl)oxy)carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Thephenyl chloroformate in step 5a of Example 5 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.07 (m, 14H), 5.70-5.30(m, 1H), 5.10- 5.01 (m, 1H), 4.70-4.55 (m, 2H), 4.32-4.07 (m, 2H), 3.72(d, J = 10.4 Hz, 1H), 3.55-3.30 (m, 1H), 2.30 (s, 3H), 1.85- 1.30 (m,4H). MS m/z (ESI): 499.1 [M + H]⁺. in step 5b did not take place. C83

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (phenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 16 in step 5bof Example 5 was replaced with phenylamine. The reaction in step 5a didnot take place. ¹H NMR (400 MHz, CD₃OD): δ 7.50-6.90 (m, 15H), 5.49-5.27 (s, 1H), 5.08 (d, J = 7.2 Hz, 1H), 4.97 (s, 1H), 4.60- 4.50 (m,1H), 4.40-4.20 (m, 1H), 3.81 (d, J = 12.4 Hz, 1H), 3.66 (d, J = 12.4 Hz,1H), 2.10-1.50 (m, 4H). MS m/z (ESI): 470.1 [M + H]⁺. C123

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (methyl(pyridine- 2-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound16 in step 5b of Example 5 was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J = 4.4Hz 1H), 8.03 (s, 1H), 7.55- 7.07 (m, 13H), 5.55-5.30 (m, 1H), 4.80-4.40(m, 3H), 4.25- 3.95 (m, 2H), 3.75-3.45 (m, 2H), 2.95-2.85 (m, 3H), 1.85-1.30 (m, 4H). MS m/z (ESI): 499.1 [M + H]⁺. did not take place. C188

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (ethyl(thiophene-3- ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound16 in step 5b of Example 5 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.54-6.91 (m, 13H), 5.56- 5.30 (m, 1H), 4.83-4.55 (m, 1H), 4.48-4.32(m, 2H), 4.29- 4.19 (m, 1H), 4.15-3.96 (m, 1H), 3.87 (d, J = 5.7 Hz,1H), 3.70 (d, J = 11.3 Hz, 1H), 3.49 (d, J = 11.9 Hz, 1H), 3.28-2.95 (m,2H), 1.86-1.73 (m, 1H), 1.59 (s, 1H), 1.52-1.40 (m, 1H), 1.35 (s, 1H),1.00 (dt, J = 13.8, 7.1 Hz, 3H). MS m/z (ESI): 518.1 [M + H ]⁺. C189

(1R,2S,5S)-8- (cyclopropyl (thiophene-3-yl- methyl) carbamoyl)-3-(2,2-diphenylacetyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 16 in step 5b of Example 5 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.50-7.45 (m, 1H), 7.40- 7.10 (m, 11H), 6.93-6.89 (m, 1H), 5.45-5.35(m, 1H), 4.60 (d, J = 14.7 Hz, 1H), 4.37 (s, 1H), 4.31 (s, 1H), 4.21 (s,1H), 4.10 (s, 1H), 3.48-3.38 (m, 2H), 2.46-2.40 (m, 1H), 2.00 (s, 1H),1.76 (s, 1H), 1.60 (s, 1H), 1.39 (s, 2H), 0.84 (d, J = 92.5 Hz, 2H),0.58 (s, 2H). MS m/z (ESI): 529.6 [M + H]⁺. C277

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (methyl((5- methylthiophen-3-yl)methyl) carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 16 in step 5b of Example 5 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 12.87 (s, 1H), 7.40-7.23 (m, 6H), 7.23-7.10 (m, 3H), 7.01 (d, J = 16.0Hz, 1H), 6.64 (s, 1H), 5.45 (s, 1H), 4.60-4.40 (m, 2H), 4.31-4.11 (m,3H), 3.71 (s, 1H), 3.50 (d, J = 12.4 Hz, 1H), 2.77-2.66 (m, 3H), 2.40(s, 3H), 2.09-1.74 (m, 1H), 1.66-1.40 (m, 2H). MS m/z (ESI): 518.1 [M +H ]⁺. C278

(1R,2S,5S)-3-(2,2- diphenylacetyl)-8- (ethyl((5- methylthiophen-2-yl)methyl) carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 16 in step 5b of Example 5 was replaced with  

¹HNMR (400 MHz, DMSO-d₆) δ 7.40-7.05 (m, 10H), 6.78- 6.73 (m, 1H),6.63-6.59 (m, 1H), 5.51-5.37 (m, 1H), 4.75- 4.32 (m, 4H), 4.13-3.84 (m,2H), 3.74-3.44 (m, 2H), 3.16- 3.02 (m, 2H), 2.37 (s, 3H), 1.85- 1.25 (m,4H), 1.02 (t, J = 7.2 Hz, 3H). MS m/z (ESI): 554.1 [M + Na]⁺. Thereaction in step 5a did not take place. C279

(1R,2S,5S)-8- (benzo[b] thiophene-3- ylmethyl)(methyl)carbamoyl)-3-(2,2- diphenylacetyl)- 3,8-diazabicyclo [3.2.1]octane-2-carboxylic acid Compound 16 in step 6 5b of Example 5 was replaced with 

  The reaction ¹HNMR (400 MHz, DMSO-d₆) 8.02-7.97 (m, 1H), 7.76- 7.68(m, 1H), 7.61-7.54 (m, 1H), 7.44-7.07 (m, 12H), 5.48- 5.32 (m, 1H),4.90-4.75 (m, 1H), 4.64-4.47 (m, 2H), 4.25- 3.90 (m, 2H), 3.86-3.45 (m,2H), 2.80-2.70 (m, 3H), 1.90- 1.10 (m, 4H). MS m/z (ESI): 554.1 [M +H]⁺. in step 5a did not take place. 23

(1R,2R,5S)-3- (diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2-carboxylic acid Compound 7 in step 3 of Example 5 was replaced with  

  The reactions ¹H NMR (400 MHz DMSO-d₆) δ 7.39 (t, J = 8.0 Hz, 4H),7.21 (t, J = 7.6 Hz, 2H), 7.07 (dd, J = 8.8, 0.8 Hz, 4H), 4.80 (s, 1H),4.33-4.15 (m, 4H), 3.90 (s, 1H), 3.57 (d, J = 12.4 Hz, 1H), 3.14 (d, J =13.2 Hz, 1H), 2.13- 1.87 (m, 3H), 1.70-1.45 (m, 1H), 1.29 (t, J = 7.2Hz, 3H). m/z (ESI): 380.1 [M + H]⁺. in the steps 5a, 5b and 6 did nottake place. C115

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8- (phenoxycarbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The reaction in step 5b didnot take place. ¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.32 (m, 6H), 7.31-7.15 (m, 4H), 7.12-7.05 (m, 2H), 7.05-6.96 (m, 3H), 4.80- 4.10 (m, 3H),3.50-3.30 (m, 2H), 2.0-1.70 (m, 3H), 1.50- MS m/z (ESI): 472.2 [M + H]⁺.C112

(1R,2S,5S)-8- (benzyl(methyl) carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. The reaction in step 5a didnot take place. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50-6.89 (m, 15H),4.51-4.13 (m, 4H), 3.91 (s, 1H), 3.45-3.25 (m, 2H), 2.70 (s, 3H),1.75-1.20 (m, 4H). MS m/z (ESI): 499.1 [M + H]⁺. C84

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8- (phenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith phenylamine. The reaction in step 5a did not take place. ¹H NMR(400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.55- 7.30 (m, 7H), 7.25-7.15 (m,2H), 7.03 (d, J = 7.6 Hz, 3H), 6.93 (t, J = 7.6 Hz, 1H), 4.85 (s, 1H),4.37 (s, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.30 (d, J = 13.2 Hz, 1H),1.85-1.30 (m, 4H). MS m/z (ESI): 471.2 [M + H]⁺. C117

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((1-phenylethyl) carbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5b ofExample 5 was replaced with Compound 23. Compound 16 was replaced with  

¹H NMR (400 MHz, CD₃OD) δ 7.37 (t, J = 8.0 Hz, 4H), 7.33- 7.25 (m, 5H),7.24-7.17 (m, 3H), 7.13-7.08 (m, 3H), 4.87- 4.80 (m, 2H), 4.60-4.50 (m,1H), 4.35-4.25 (m, 1H), 3.60- 3.45 (m, 2H), 1.85-1.50 (m, 4H), 1.42 (d ,J = 6.8 Hz, 3H). MS m/z (ESI): 499.1 [M + H]⁺. The reaction in step 5adid not take place. C118

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(phenyl) carbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5b ofExample 5 was replaced with Compound 23. Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.4-7.25 (m, 6H), 7.20-7.10 (m, 5H), 7.0-6.90 (m, 4H), 4.35-4.10 (m, 2H), 3.69 (s, 1H), 3.08 (s, 3H), 3.01 (d, J= 11.2 Hz, 1H), 2.8 (d, J = 11.6 Hz, 1H), 1.60-1.10 (m, 4H). MS m/z(ESI): 484.8 [M + H]⁺. The reaction in step 5a did not take place. C124

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(pyridine- 3-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. 1H NMR (400 MHz, DMSO-d₆)δ 8.80 (d, J = 5.2 Hz, 1H), 8.74 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H),8.00- 7.90 (m, 1H), 7.36 (t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H),7.01 (d, J = 7.6 Hz, 4H), 4.56 (d, J = 15.6 Hz, 1H), 4.45- 4.20 (m, 3H),3.99 (s, 1H), 3.45- 3.30 (m, 2H), 2.84 (s, 3H), 1.80-1.20 (m, 4H). MSm/z (ESI): 500.1 [M + H]⁺. C125

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(pyridine- 4-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 8.76 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 5.6 Hz, 2H), 7.36 (t, J = 7.6Hz, 4H), 7.16 (t, J = 7.6 Hz, 2H), 7.02 (d, J = 8.0 Hz, 4H), 4.64 (d, J= 17.2 Hz, 1H), 4.49 (d, J = 16.8 Hz, 1H), 4.45-4.20 (m, 2H), 4.01 (s,1H), 3.50- 3.30 (m, 2H), 2.87 (s, 3H), 1.80- 1.20 (m, 4H). MS m/z (ESI):500.1 [M + H]⁺. C126

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(pyridine- 2-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a ¹HNMR (400 MHz, DMSO-d₆) δ 7.2 Hz, 1H), 7.36(t, J = 7.6 Hz, 4H), 7.17 (t, J = 7.4 Hz, 2H), 7.01 (d, J = 7.9 Hz, 4H),4.65 (d, J = 16.3 Hz, 1H), 4.48 (d, J = 16.2 Hz, 2H), 4.38 (s, 2H), 4.03(s, 2H), 3.47-3.33 (m, 2H), 2.90 (s, 3H), 1.67 (s, 1H), 1.55 (s, 1H),1.37 (s, 1H), 1.27-1.10 (m, 1H). MS m/z (ESI): 500.1 [M + H]⁺. did nottake place. C128

(1R,2S,5S)-8- (benzyl(2,2,2- trifluoroethyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹HNMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 7.50-6.93 (m, 15H), 4.70 (d, J= 15.3 Hz, 1H), 4.42 (s, 1H), 4.29 (d, J = 15.2 Hz, 1H), 4.13 (dd, J =15.7, 9.9 Hz, 1H), 4.04 (s, 1H), 3.58- 3.44 (m, 2H), 3.40 (s, 1H), 1.68(s, 1H), 1.47 (s, 2H), 1.34-1.11 (m, 1H). MS m/z (ESI): 567.2 [M + H]⁺.The reaction in step 5a did not take place. C129

(1R,2S,5S)-8- (benzyl(methyl) carbamoyl)-3- (bis(4-fluorophenyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7in step 3 of Example 5 was replaced with  

  The ¹HNMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 7.62-6.95 (m, 13H), 4.45(d, J = 15.4 Hz, 1H), 4.42-4.30 (m, 2H), 4.26 (d, J = 15.2 Hz, 1H), 3.93(s, 1H), 3.42 (d, J = 12.1 Hz, 2H), 2.70 (s, 3H), 1.76 (s, 1H),1.66-1.53 (m, 1H), 1.46 (s, 1H), 1.37- 1.22 (m, 1H). MS m/z (ESI): 535.0[M + H]⁺. reaction in step 5a did not take place. C130

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(isoindoline-2- carbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5b ofExample 5 was replaced with Compound 23. Compound 16 was replaced withisoindoline. The reaction in step 5a did not take place. ¹HNMR (400 MHz,DMSO-d₆) δ 12.97 (s, 1H), 7.46-6.98 (m, 14H), 4.87-4.76 (m, 2H), 4.54(d, J = 14.2 Hz, 3H), 4.34 (s, 1H), 4.15 (s, 1H), 3.47 (s, 2H), 1.74 (s,1H), 1.67-1.51 (m, 1H), 1.41 (s, 1H), 1.33-1.21 (m, 1H). MS m/z (ESI):497.2 [M + H]⁺. C131

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(1,2,3,4- tetrahydroisoquinoline-2-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with tetrahydroisoquinoline. The reaction in step 5a didnot take place. ¹HNMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 7.50-6.91 (m,14H), 4.51-4.25 (m, 4H), 3.95 (s, 1H), 3.61-3.51 (m, 1H), 3.51-3.35 (m,3H), 2.88-2.65 (m, 2H), 1.68 (s, 1H), 1.56 (s, 1H), 1.37 (s, 1H),1.27-1.10 (m, 1H). MS m/z (ESI): 511.1 [M + H]⁺. C132

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4-phenylpiperazine-1-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with 1-phenylpiperazine. The reaction in step 5a did nottake place. ¹HNMR (400 MHz, DMSO-d₆) δ 7.36 (t, J = 7.7 Hz, 4H), 7.20(dt, J = 14.7, 7.7 Hz, 4H), 6.98 (dd, J = 27.6, 8.0 Hz, 6H), 6.82 (t, J= 7.2 Hz, 1H), 4.46-4.23 (m, 2H), 3.91 (s, 1H), 3.56- 3.28 (m, 6H),3.22-3.00 (m, 4H), 1.70 (s, 1H), 1.55 (s, 1H), 1.46-1.09 (m, 2H). MS m/z(ESI): 540.1 [M + H]⁺. C133

(1R,2S,5S)-8- (dibenzylcarbamoyl)- 3- (diphenylcarbamoyl)-3,8-diazabicyclo[3.2.1] octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23; Compound 16 was replacedwith dibenzylamine; and the reaction condition was changed to reactingin a sealed tube at 50° C. for 50 hours. The reaction in step 5a did nottake place. ¹HNMR (400 MHz, DMSO-d₆) δ 13.1 (s, 1H), 7.45-7.25 (m, 10H),7.20-7.10 (m, 6H), 7.05- 6.95 (m, 4H), 4.55-4.30 (m, 4H), 4.10-3.95 (m,3H), 3.45- 3.35 (m, 2H), 1.80-1.20 (m, 4H). MS m/z (ESI): 575.0 [M +H]⁺. C134

(1R,2S,5S)-8- (benzyl(phenyl) carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

¹H NMR (400 MHz, DMSO-d₆) δ 7.35-7.28 (m, 5H), 7.27- 7.20 (m, 4H),7.20-7.10 (m, 4H), 7.11-7.02 (m, 3H), 7.00- 6.90 (m, 4H), 4.85-4.70 (m,2H), 4.40 (s, 1H), 4.20 (s, 1H), 3.71 (s, 1H), 2.98 (d, J = 12.8 1Hz,1H), 2.75 (d, J = 12.0 Hz, H), 1.70-1.20 (m, 4H). MS m/z (ESI): 561.0[M + H]⁺. The reaction in step 5a did not take place. C135

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3-phenylazetidine-1-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The ¹HNMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 7.43-6.95 (m, 15H), 4.46(s, 1H), 4.36-4.20 (m, 3H), 4.10 (s, 1H), 3.95- 3.72 (m, 4H), 3.42 (d, J= 11.9 Hz, 1H), 1.68-1.50 (m, 2H), 1.41-1.20 (m, 2H). MS m/z (ESI):510.6 [M + H]⁺. reaction in step 5a did not take place. C136

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3-phenylpiperidine-1-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a ¹HNMR (400 MHz DMSO-d₆) δ 12.95 (s, 1H),7.50-6.93 (m, 15H), 4.34 (s, 2H), 3.91-3.68 (m, 3H), 3.50-3.27 (m, 2H),2.90-2.77 (m, 1H), 2.76-2.64 (m, 2H), 1.88 (d, J = 11.1 Hz, 1H),1.75-1.62 (m, 3H), 1.59- 1.47 (m, 2H), 1.46-1.31 (m, 2H). MS m/z (ESI):539.1 [M + H]⁺. did not take place. C137

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3- phenylpyrrolidine-1-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a 1HNMR (400 MHz, DMSO-d₆) δ 13.00 (s, 1H),7.62-6.87 (m, 15H), 4.44 (d, J = 18.7 Hz, 1H), 4.30 (s, 1H), 4.11-3.96(m, 1H), 3.80-3.67 (m, 1H), 3.60- 3.52 (m, 1H), 3.52-3.42 (m, 2H),3.41-3.32 (m, 2H), 3.29- 3.21 (m, 1H), 2.22-2.12 (m, 1H), 1.96-1.79 (m,1H), 1.71 (s, 1H), 1.62 (s, 1H), 1.57-1.46 (m, 1H), 1.36 (s, 1H). MS m/z(ESI): 524.6 [M + H]⁺. did not take place. C138

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(2- phenylpyrrolidine-1-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹HNMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H), 7.59-6.96 (m, 15H), 4.88-4.78(m, 1H), 4.51- 4.11 (m, 2H), 3.95 (s, 1H), 3.71-3.52 (m, 2H), 3.51-3.44(m, 1H), 3.43-3.36 (m, 2H), 2.31-2.18 (m, 1H), 1.98-1.64 (m, 3H),1.59-1.49 (m, 2H), 1.47-1.07 (m, 3H). MS m/z (ESI): 525.1 [M + H]⁺. Thereaction in step 5a did not take place. C145

(1R,2S,5S)-8- (bis(4-fluorophenyl) carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

  The ¹HNMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 7.64-6.89 (m, 18H),4.35-4.15 (m, 2H), 3.97 (s, 1H), 3.56 (s, 2H), 3.19 (d, J = 9.1 Hz, 1H),2.94 (d, J = 12.0 Hz, 1H), 1.72-1.61 (m, 1H), 1.54 (s, 1H), 1.35 (s,1H), 1.26- 1.06 (m, 1H). MS m/z (ESI): 583.1 [M + H]⁺. reaction in step5a did not take place. C147

(1R,2S,5S)-8- ((cyclohexylmethyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (t, J = 7.6Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H), 7.01 (t, J = 7.6 Hz, 4H), 4.35-4.15(m, 2H), 3.85 (s, 1H), 3.45-3.30 (m, 2H), 3.29- 3.15 (m, 1H), 2.85-2.70(m, 4H), 1.70-1.35 (m, 9H), 1.25- 1.05 (m, 4H), 0.85-0.7 (m, 2H). MS m/z(ESI): 505.2 [M + H]⁺. did not take place. C149

(1R,2S,5S)-8- ((2-chlorobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 8.10-7.95 (m, 1H), 7.70-7.29 (m, 6H), 7.27-7.12 (m, 3H), 7.07-6.95 (m, 3H), 6.80-6.65 (m, 2H), 4.80- 4.20 (m, 4H),3.91 (s, 1H), 3.50-3.30 (m, 2H), 2.76 (s, 3H), 1.80-1.20 (m, 4H). MS m/z(ESI): 533.0 [M + H]⁺. The reaction in step 5a did not take place. C151

(1R,2S,5S)-8- ((3-chlorobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹HNMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 7.42-6.98 (m, 14H), 4.42 (d, J= 15.3 Hz, 2H), 4.37 (s, 1H), 4.27 (d, J = 15.4 Hz, 1H), 3.94 (s, 1H),3.48- 3.36 (m, 2H), 2.74 (s, 3H), 1.72 (s, 1H), 1.56 (s, 1H), 1.46-1.33(m, 1H), 1.32-1.13 (m, 1H). MS m/z (ESI): 533.1 [M + H]⁺. The reactionin step 5a did not take place. C150

(1R,2S,5S)-8- ((4-chlorobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

1HNMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H), 7.45-6.94 (m, 14H), 4.47-4.32(m, 2H), 4.29- 4.07 (m, 2H), 3.92 (s, 1H), 3.42 (d, J = 12.0 Hz, 2H),2.71 (s, 3H), 1.67 (s, 1H), 1.56 (s, 1H), 1.39 (s, 1H), 1.29-1.14 (m,1H). MS m/z (ESI): 532.8 [M + H]⁺. The reaction in step 5a did not takeplace. C179

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(2- phenylazetidine-1-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20in step 5b of Example 5 was replaced with Compound 23. Compound 16 wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.35-7.20 (m, 10H), 7.15-7.00 (m, 5H),5.25-5.05 (m, 1H), 4.50-4.35 (m, 1H), 4.15-3.95 (m, 3H), 3.85-3.75 (m,1H), 3.30-3.15 (m, 2H), 2.05-1.85 (m, 2H), 1.60-1.15 (m, 4H). MS m/z(ESI): 511.1 [M + H]⁺. The reaction in step 5a did not take place. C152

(1R,2S,5S)-8-(benzyl (isopropyl)carbamoyl)- 3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

¹HNMR (400 MHz, DMSO-d₆) δ 13.03 (s, 1H), 7.45-6.89 (m, 15H), 4.40 (d, J= 15.9 Hz, 1H), 4.35-4.20 (m, 2H), 4.14 (d, J = 16.0 Hz 1H), 4.09-4.01(m, 1H), 3.91 (s, 1H), 3.56-3.45 (m, 2H), 1.57 (s, 1H), 1.44 (s, 1H),1.38-1.28 (m, 1H), 1.27- 1.16 (m, 1H), 1.07 (dd, J = 14.6, 6.5 Hz, 6H).MS m/z (ESI): 526.8 [M + H]⁺. The reaction in step 5a did not takeplace. C153

(1R,2S,5S)-8-(benzyl (cyclopropyl) carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

¹H NMR (400 MHz, DMSO-d₆) δ 13.00 (s, 1H), 7.45-6.93 (m, 15H), 4.68 (d,J = 15.0 Hz, 1H), 4.48 (s, 1H), 4.41-4.26 (m, 1H), 4.15 (s, 1H), 4.04(d, J = 15.1 Hz, 1H), 3.51-3.42 (m, 2H), 2.45-2.32 (m, 1H), 1.69 (s,1H), 1.57-1.28 (m, 3H), 0.79-0.68 (m, 1H), 0.67-0.58 (m, 1H), 0.57-0.46(m, 2H). MS m/z (ESI): 524.8 [M + H]⁺. The reaction in step 5a did nottake place. C154

(1R,2S,5S)-8-(benzyl (cyclopropylmethyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 7.41-6.96 (m, 15H),4.65 (d, J = 15.5 Hz, 1H), 4.38-4.12 (m, 3H), 3.90 (s, 1H), 3.43 (d, J =12.1 Hz, 2H), 1H), 1.53 (s, 1H), 1.41-1.31 (m, 1H), 1.28-1.15 (m, 1H),0.99-0.87 (m, 1H), 0.47-0.30 (m, 2H), 0.06 (d, J = 4.7 Hz, 2H). MS m/z(ESI): 538.9 [M + H]⁺. reaction in step 5a did not take place. C155

(1R,2S,5S)-8-(benzyl (ethyl)carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 7.43-6.89 (m,15H), 4.51 (d, J = 15.6 Hz, 1H), 4.36-4.20 (m, 2H), 3.90 (s, 1H), 3.39(dd, J = 32.0, 11.7 Hz, 3H), 3.24-3.13 (m, 1H), 3.05-2.93 (m, 1H), 1.68(s, 1H), 1.62-1.49 (m, 1H), 1.47- 1.32 (m, 1H), 1.29-1.10 (m, 1H), 0.98(t, J = 7.0 Hz, 3H). MS m/z (ESI): 512.8 [M + H]⁺. in step 5a did nottake place. C182

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(phenylsulfulyl)-3,8- diazabicyclo[3.2.l]octane-2- carboxylic acid Compound 20 in step 5a of Example 5 wasreplaced with Compound 23.  

  was replaced with ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (d, J = 7.6 Hz,2H), 7.68 (t, J = 6.4 Hz, 1H), 7.57 (t, J = 7.2 Hz, 2H), 7.33 (t, J =7.6 Hz, 4H), 7.15 (t, J = 7.2 Hz, 2H), 6.99 (d, J = 8.0 Hz, 4H), 4.52(s, 1H), 4.37- 4.27 (m, 1H), 4.14 (s, 1H), 3.39- 3.34 (m, 1H), 3.16 (d,J = 12.0 Hz, 1H), 1.35-1.00 (m, 4H). MS m/z (ESI): 492.0 [M + H]⁺.benzene sulfonyl chloride. TEA was replaced with DIPEA. DCM was replacedwith DCE. The reaction in step 5b did not take place. C159

(1S,2R,5R)-8-(benzyl (methyl)carbamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 5 in step 1of Example 5 was replaced with compound 6*. Compound 7 in step 3 wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.30 (m, 6H), 7.29-7.12 (m, 5H), 7.05-6.95 (m, 4H), 4.45 (d, J = 15.6 Hz, 1H), 4.40-4.30 (m, 2H), 4.26 (d, J =15.6 Hz, 1H), 3.93 (s, 1H), 3.50-3.42 (m, 2H), 2.70 (s, 3H), 1.80-1.20(m, 4H). MS m/z (ESI): 498.9 [M + H]⁺. The reaction in step 5a did nottake place. C139

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((S)-2- phenylpyrrolidine-1-carbonyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a ¹H NMR (300 MHz, DMSO-d₆) δ 13.11 (s, 1H),7.45-6.84 (m, 15H), 4.82 (t, J = 7.2 Hz, 1H), 4.44 (s, 1H), 4.22 (s,1H), 3.92 (s, 1H), 3.61-3.48 (m, 2H), 3.20 (d, J = 11.9 Hz, 1H), 2.27-2.13 (m, 1H), 1.85-1.67 (m, 2H), 1.58-1.46 (m, 1H), 1.45- 1.34 (m, 2H),1.28-1.06 (m, 2H). MS m/z (ESI): 525.1 [M + H]⁺. did not take place.C140

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((R)-2- phenylpyrrolidine-1-carbonyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 7.56-6.93 (m, 15H), 4.85 (t,J = 7.6 Hz, 1H), 4.42-4.22 (m, 2H), 4.18 (s, 1H), 3.72-3.60 (m, 1H),3.54- 3.46 (m, 2H), 2.39-2.21 (m, 2H), 1.84 (s, 1H), 1.79-1.67 (m, 1H),1.62-1.45 (m, 2H), 1.42-1.26 (m, 2H). MS m/z (ESI): 525.2 [M + H]⁺. Thereaction in step 5a did not take place. C161

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((4-fluorobenzyl)(methyl)carbamoyl)- 3,8-thazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 7.41-6.96 (m, 14H), 4.43-4.22(m, 4H), 3.92 (s, 1H), 3.47-3.33 (m, 2H), 2.70 (s, 3H), 1.77-1.35 (m,4H). MS m/z (ESI): 517.1 [M + H]⁺. The reaction in step 5a did not takeplace. C162

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(4- methylbenzyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (t, J = 8.0 Hz, 4H), 7.20-7.10 (m, 4H),7.07 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.6 Hz, 4H), 4.45-4.25 (m, 3H),4.21 (d, J = 15.2 Hz, 1H), 3.91 (s, 1H), 3.45-3.35 (m, 2H), 2.68 (s,3H), 2.28 (s, 3H), 1.75-1.30 (m, 4H). MS m/z (ESI): 513.1 [M + H]⁺. Thereaction in step 5a did not take place. C165

(1R,2S,5S)-8- ((4-bromobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 Hz, DMSO-d₆) δ 12.97 (s, 1H), 7.57-6.97 (m, 14H), 4.45-4.19(m, 4H), 3.93 (s, 1H), 3.48-3.36 (m, 2H), 2.71 (s, 3H), 1.77-1.32 (m,4H). MS m/z (ESI): 576.7 [M + H]⁺. The reaction in step 5a did not takeplace. C165-1

(1R,2R,5S)-ethyl 8-((4-bromobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylateCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

MS m/z (ESI): 604.6 [M + H]+. The reactions in the steps 5a and 6 werenot performed. C166

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4-methoxylbenzyl)(methyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 7.41-6.85 (m, 14H), 4.36 (d,J = 14.6 Hz, 2H), 4.18 (d, J = 14.8 Hz, 1H), 3.90 (s, 1H), 3.73 (s, 3H),3.62-3.47 (m, 3H), 2.66 (s, 3H), 1.72 (s, 1H), 1.62-1.46 (m, 1H), 1.45-1.12 (m, 2H). MS m/z (ESI): 528.8 [M + H]⁺. The reaction in step 5a didnot take place. C191

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(pyrimidine-2-yl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid In step 5a of Example 5, Compound 20was replaced with Compound 23, phenyl chloroformate was replaced with2-chloropyrimidine, TEA was replaced with DIPEA, and DCM was replacedwith NMP; ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 7.39 (t, J = 7.2 Hz,4H), 7.24 (t, J = 7.2 Hz, 2H), 7.13 (d, J = 8.0 Hz, 4H), 7.00 (s, 1H),5.34 (s, 1H), 4.8-4.7 (m, 2H), 3.72 (d, J = 12.4 Hz, 1H), 3.39 (d, J =12.4 Hz, 1H), 2.15-1.95 (m, 2H), 1.90-1.70 (m, 2H). MS m/z (ESI): 430.0[M + H]⁺. and the reaction condition was changed to reacting at 130° C.for 16 hours. The reaction in step 5b did not take place. C184

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(thiophene- 3-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 7.49 (dd, J = 4.9, 2.9 Hz,1H), 7.41-7.28 (m, 5H), 7.17 (t, J = 7.4 Hz, 2H), 7.05-6.92 (m, 5H),4.42-4.20 (m, 4H), 3.92 (s, 1H), 3.39 (dd, J = 24.8, 11.6 Hz, 2H), 2.70(d, J = 3.0 Hz, 3H), 1.77-1.63 (m, 1H), 1.60-1.47 (m, 1H), 1.44- 1.15(m, 2H). MS m/z (ESI): 504.6 [M + H]⁺. The reaction in step 5a did nottake place. C169

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl(4- trifluoromethyl)benzyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d, J = 8.0 Hz, 2H), 7.41 (d, J =8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.6 Hz, 2H), 7.01(d, J = 7.6 Hz, 4H), 4.51 (d, J = 16.0 Hz, 1H), 4.45-4.30 (m, 3H), 3.95(s, 1H), 3.45-3.20 (m, 2H), 2.75 (s, 3H), 1.80- 1.30 (m, 4H). MS m/z(ESI): 566.8 [M + H]⁺. reaction in step 5a did not take place. C146

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(2-phenylpiperidine-1-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (s, 1H), 7.54-6.90 (m, 12H), 5.13 (d,J = 32.5 Hz, 1H), 4.44-4.17 (m, 2H), 3.98 (s, 1H), 3.80 (s, 1H),3.71-3.58 (m, 1H), 3.41-3.53 (m, 2H), 2.90-2.69 (m, 1H), 2.36-2.21 (m,1H), 1.85-1.66 (m, 2H), 1.63-1.41 (m, 3H), 1.39-1.14 (m, 3H). MS m/z(ESI): 538.8 [M + H]⁺. The reaction in step 5a did not take place. C143

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((R)-2- (p-tolyl)pyrrolidine-1-carbonyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.40-7.32 (m, 4H), 7.20-7.12 (m, 2H), 7.10-6.95 (m, 8H), 4.85-4.75 (m, 1H), 4.47-4.32 (m, 1H), 4.27- 4.02 (m, 1H),3.92 (s, 1H), 3.65- 3.52 (m, 2H), 3.40-3.15 (m, 2H), 2.27-2.12 (m, 4H),1.87- 1.65 (m, 3H), 1.60-1.20 (m, 4H). MS m/z (ESI): 538.6 [M + H]⁺. Thereaction in step 5a did not take place. C213

(1R,2S,5S)-8-((4- cyclopropylbenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did ¹H NMR (400 MHz, DMSO-d₆) δ 13.40-12.85(m, 1H), 7.34 (t, J = 7.8 Hz, 4H), 7.15 (t, J = 7.4 Hz, 2H), 7.06- 6.97(m, 8H), 4.37 (d, J = 15.1 Hz, 2H), 4.20 (d, J = 15.1 Hz, 1H), 3.90 (s,1H), 3.50-3.37 (m, 2H), 2.67 (s, 3H), 1.95- 1.83 (m, 1H), 1.68 (s, 1H),1.55 (s, 1H), 1.46-1.32 (m, 1.27-1.09 (m, 2H), 0.95- 0.89 (m, 2H),0.67-0.58 (m, 2H). MS m/z (ESI): 538.7 [M + H]⁺. not take place. C214

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((4-isopropylbenzyl)(methyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (t, J = 7.6 Hz, 4H), 7.19 (d, J = 8.0Hz, 2H), 7.17-7.06 (m, 4H), 7.03 (d, J = 7.6 Hz, 4H), 4.39 (d, J = 14.8Hz, 2H), 4.25 (d, J = 15.2 Hz, 2H), 3.92 (s, 1H), 3.37 (s, 2H),2.90-2.80 (m, 1H), 2.70 (s, 3H), 1.57 (s, 2H), 1.42 (s, 2H), 1.18 (d, J= 6.9 Hz, 6H). MS m/z (ESI): 541.3 [M + H]⁺. The reaction in step 5a didnot take place. C144

(1R,2S,5S)-8-((R)-2- (4-chlorphenyl) pyrrolidine- 1-carbonyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.26 (m, 6H), 7.23-7.12 (m, 4H), 7.05-6.95 (m, 4H), 4.82 (t, J = 7.2 Hz, 1H), 4.50-3.90 (m, 3H), 3.70-3.53 (m,2H), 3.45-3.35 (m, 1H), 3.23 (d, J = 10.8 Hz, 1H), 2.30-2.15 (m, 1H),1.90- 1.65 (m, 2H), 1.55-1.20 (m, 5H). MS m/z (ESI): 559.1 [M + H]⁺. Thereaction in step 5a did not take place. C216

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl(4- methylbenzyl)carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 12.996 (brs, 1H), 7.35 (t, J = 8.0 Hz, 4H), 7.17 (t, 8.0 Hz, 2H), 7.08(d, J = 8.0 Hz, 2H), 7.01 (d, J = 7.6 Hz, 4H), 4.46 (d, J = 15.2 Hz,1H), 4.41-4.22 (m, 2H), 4.19 (d, J = 15.2 Hz, 1H), 3.88 (s, 1H), (m,1H), 3.01-2.90 (m, 1H), 2.28 (s, 3H), 1.75-1.25 (m, 4H), 0.97 (t, J =6.8 Hz, 3H). MS m/z (ESI): 526.7 [M + H]⁺. C217

(1R,2S,5S)-8- ((4-chlorobenzyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.42-7.30 (m, 6H), 7.22 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 7.2 Hz, 2H),7.01 (d, J = 7.6 Hz, 4H), 4.48 (d, J = 16.0 Hz, 1H), 4.41-4.26 (m, 2H),4.25 (d, J = 15.6 Hz, 1H), 3.90 (s, 1H), 3.42 (d, J = 12.0 Hz, 1H),3.30-3.15 (m, 2H), 3.05-2.90 (m, 1H), 1.70-1.28 (m, 4H), 0.98 (t, J =7.2 Hz, 3H). MS m/z (ESI): 546.8 [M + H]⁺. C219

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl(2- methylbenzyl)carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.02 (s, 1H), 7.35 (t, J = 7.9 Hz, 4H), 7.21-7.06 (m, 6H), 7.01 (d, J= 7.5 Hz, 4H), 4.55 (d, J = 15.6 Hz, 1H), 4.33 (s, 1H), 4.18 (d, J =15.6 Hz, 1H), 3.89 (s, 1H), 3.41-3.28 (m, 3H), 3.25 3.14 (m, 1H), 2.96-2.85 (m, 1H), 2.17 (s, 3H), 1.77- 1.64 (m, 1H), 1.58-1.46 (s, 1H),1.45-1.33 (m, 1H), 1.29- 1.22 (m, 1H), 0.94 (t, J = 7.0 Hz, 3H). MS m/z(ESI): 526.7 [M + H]⁺. C212

(1R,2S,SS)-8- ((2-chlorobenzyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.03 (s, 1H), 7.46-7.14 (m, 10H), 7.04-6.98 (m, 4H), 4.61 (d, J =16.0 Hz, 1H), 4.33 (s, 1H), 4.26 (d, J = 16.0 Hz, 2H), 3.90 (s, 1H),3.42 (d, J = 12.9 Hz, 2H), 3.26 (dd, J = 14.1, 7.1 Hz, 1H), 3.02 (dd, J= 14.2, 7.0 Hz, 1H), 1.74-1.61 (m, 1H), 1.59-1.47 (m, 1H), 1.44-1.32 (m,1H), 1.28-1.16 (m, 1H), 0.99 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 546.7[M + H]⁺. C210

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4- phenylpyrimidine- 2-yl)-3,8-diazabicyclo[3.2.1] octane-2- carboxylic acid In step 5a of Example 5,Compound 20 was replaced with Compound 23, phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J = 5.2 Hz, 1H), 8.17-8.10 (m, 2H),7.55-7.45 (m, 3H), 7.37 (t, J = 8.0 Hz, 4H), 7.28 (d, J = 5.2 Hz, 1H),7.18 (t, J = 7.2 Hz, 2H), 7.07-7.00 (m, 4H), 5.33 (s, 1H), 4.88 (s, 1H),4.38 (s, 1H), 3.56 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 11.6 Hz, 1H),1.81- 1.61 (m, 2H), 1.50-1.30 (m, 2H). MS m/z (ESI): 505.8 [M + H]⁺. TEAwas replaced with DIPEA and DCM was replaced with NMP; and the reactioncondition was changed to reacting at 130° C. for 16 hours. The reactionin step 5b did not take place. C253

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4- phenylquinazoline- 2-yl)-3,8-diazabicyclo[3.2.1] octane-2- carboxylic acid In step 5a of Example 5,Compound 20 was replaced with Compound 23, phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.86-7.74 (m, 4H), 7.66- 7.56 (m, 4H),7.40-7.30 (m, 5H), 7.19 (t, J = 7.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 4H),5.42 (s, 1H), 4.97 (s, 1H), 4.42 (s, 1H), 3.60 (d, J = 13.2 Hz, 1H),3.50- 3.40 (m, 1H), 1.86-1.65 (m, 2H), 1.61-1.40 (m, 2H). MS m/z (ESI):556.1 [M + H]⁺. TEA was replaced with DIPEA, and DCM was replaced withNMP; and the reaction condition was changed to reacting at 130° C. for16 hours. The reaction in step 5b did not take place. C173

(1R,2S,5S)-8- (benzyl(methyl) carbamoyl)-3-(2,2- diphenylpropionyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7 in step 3of Example 5 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J = 7.26 Hz, 2H), 7.45-7.10 (m,13H), 4.77 (d, J = 2.8 Hz, 1H), 4.45-4.05 (m, 3H), 3.52 (d, J = 5.6 Hz,1H), 3.20-3.05 (m, 2H), 2.72-2.57 (m, 3H), 1.85-1.51 (m, 4H), 1.30-1.00(m, 3H). MS m/z (ESI): 511.8 [M + H]⁺. The reaction in step 5a did nottake place. C192

(1R,2S,5S)-8- (benzyl(methyl) carbamoyl)-3-(bis (2-methoxylphenyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 7in step 3 of Example 5 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 12.53 (brs, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.28- 7.22 (m, 1H),7.21-7.11 (m, 4H), 7.07-7.00 (m, 2H), 6.85 (t, J = 7.6 Hz, 2H),6.82-6.75 (m, 2H), 4.49-4.38 (m, 2H), 4.37-4.31 (m, 1H),4.23 (d, J =15.2 Hz, 1H), 3.87 (s, 1H), 3.70 (s, 6H), 3.41 (d, J = 11.6 Hz, 1H),3.25 (d, J = 11.2 Hz, 1H), 2.68 (s, 3H), 1.85-1.71 (m, 1H), 1.61-1.31(m, 3H). MS m/z (ESI): 558.7 [M + H]⁺. C171

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((4-ethynylbenzyl)(methyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The 1H NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J = 8.0 Hz, 2H), 7.35 (t, J =8.0 Hz, 4H), 7.25-7.05 (m, 4H), 7.01 (d, J = 7.6 Hz, 4H),4.45 (d, J =15.6 Hz, 1H), 4.38-4.30 (m, 2H), 4.27 (d, J = 15.6 Hz, 1H), 4.17 (s,1H), 3.93 (s, 1H), 3.45-3.34 (m, 2H), 2.71 (s, 3H), 1.77-1.65 (m, 1H),1.60-1.46 (m, 1H), 1.45- 1.20 (m, 1H). MS m/z (ESI): 523.0 [M + H]⁺.reaction in step 5a did not take place. C220

(1R,2S,5S)-8- ((2,4-dichlorobenzyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.35-7.0 (m, 20H), 5.49 (s, 1H), 5.37 (s,1H), 5.14 (s, 1H), 4.73 (s, 1H), 4.57 (s, 1H), 3.75- 3.45 (m, 2H),2.25-2.0 (m, 1H), 1.95-1.50 (m, 3H). MS m/z (ESI): 544.9 [M + H]⁺. Thereaction in step 5a did not take place. C196

(1R,2S,5S)-8- (cyclopropyl (thiophene-3-yl- methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 7.60-6.89 (m, 13H), 4.61 (d,J = 15.1 Hz, 1H), 4.46 (s, 1H), 4.31 (s, 1H), 4.18- 4.04 (m, 2H), 3.43(s, 2H), 2.43 (s, 1H), 1.68 (s, 1H), 1.54-1.33 (m, 2H), 1.26-1.14 (m,1H), 0.78-0.66 (m, 1H), 0.64-0.42 MS m/z (ESI): 531.0 [M + H]⁺. Thereaction in step 5a did not take place. C205

(1R,2S,5S)-8- ((cyclopropylmethyl) (thiophene-3- ylmethyl)carbamoyl)- 3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.04 (s, 1H), 7.48 (dd, J = 4.9, 2.9 Hz, 1H), 7.41-7.27 (m, 5H), 7.17(t, J = 7.4 Hz, 2H), 7.01 (d, J = 7.6 Hz, 4H), 6.94 (d, J = 4.9 Hz, 1H),4.58 (d, J = 15.4 Hz, 1H), 4.33 (d, J = 15.3 Hz, 3H), 3.89 (s, 1H),3.48-3.27 (m, 2H), 3.04-2.87 (m, 2H), 1.69 (s, 1H), 1.53 (s, 1H), 1.43-1.31 (m, 1H), 1.27-1.15 (m, 1H), 0.95 (s, 1H), 0.45-0.30 (m, 2H), 0.09(d, J = 4.6 Hz, 2H). MS m/z (ESI): 544.6 [M + H]⁺. C255

(1R,2S,5S)-8- ((6-chloropyridine- 3-yl)methyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.00 (s, 1H), 8.26 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (d, J =8.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 4H), 7.16 (t, J = 7.2 Hz, 2H), 7.01(d, J = 7.6 Hz, 4H), 4.42 (d, J = 15.6 Hz, 1H), 4.35 (s, 1H), 4.28 (d, J= 15.2 Hz, 1H), 3.94 (s, 2H), 3.44-3.34 (m, 3H), 2.74 (s, 3H), 1.69 (s,1H), 1.54 (s, 1H), 1.37 (s, 1H), 1.24 (s, 1H). MS m/z (ESI): 534.1 [M +H]⁺. C206

(1R,2S,5S)-8- (cyclopropyl(thiazole- 4-ylmethyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J = 2.0 Hz, 1H), 7.45- 7.31 (m,5H), 7.17 (t, J = 7.2 Hz, 2H), 7.01 (d, J = 7.6 Hz, 4H), 4.80 (d, J =15.6 Hz, 1H), 4.50-4.25 (m, 2H), 4.22 (d, J = 15.6 Hz, 1H), 3.50-3.30(m, 2H), 2.6-2.51 (m, 1H), 1.75- 1.20 (m, 4H), 0.75-0.50 (m, 4H). MS m/z(ESI): 520.0 [M + H]⁺. The reaction in step 5a did not take place. C207

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl (thiophene-3-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.05 (s, 1H), 7.48 (dd, J = 4.8 Hz, 2.8 Hz, 1H), 7.35 (t, J = 8.0 Hz,4H), 7.30 (d, J = 1.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 2H), 7.01 (d, J =7.6 Hz, 4H), 6.95 (dd, J = 4.8, 1.2 Hz, 1H), 4.43 (d, J = 15.2 Hz, 1H),4.40- 4.26 (m, 2H), 4.23 (d, J = 15.2 Hz, 1H), 3.89 (s, 1H), 3.49- 3.34(m, 2H), 3.25-3.12 (m, 1H), 3.05-2.94 (m, 1H), 1.75- 1.19 (m, 4H), 0.98(t, J = 6.8 Hz, 3H). MS m/z (ESI): 519.0 [M + H]⁺. C218

(1R,2S,5S)-8- ((4-chlorobenzyl) (cyclopropylmethyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 7.41-7.30 (m, 6H), 7.25-7.11(m, 4H), 7.05- 6.98 (m, 4H), 4.61 (d, J = 15.7 Hz, 1H), 4.38-4.22 (m,3H), 3.91 (s, 1H), 3.39 (dd, J = 39.5, 11.8 Hz, 2H), 3.07-2.89 (m, 2H),1.69 (s, 1H), 1.52 (s, 1H), 1.37 (s, 1H), 1.24 (s, 1H), 0.92 (s, 1H),0.44-0.31 (m, 2H), 0.12-0.04 (m, 2H). MS m/z (ESI): 573.1 [M + H]⁺. Thereaction in step 5a did not take place. C209

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl(thiazole- 4-ylmethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 9.06 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 8.0Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H),7.01 (d, J = 7.2 Hz, 4H), 4.57 (d, J =15.6 Hz, 1H), 4.41 (d, J = 15.6 Hz, 1H),4.39-4.20 (m, 2H), 4.04 (s, 1H),3.45- 3.30 (m, 2H), 3.25-3.16 (m, 1H), 3.13-3.04 (m, 1H), 1.80- 1.20 (m,4H), 0.99 (t, J = 7.2 Hz, 3H). MS m/z (ESI): 520.1 [M + H]⁺. C180

(1R,2S,5S)-8- (N-benzyl-N- methylsulphamoyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5bof Example 5 was replaced with Compound 23. Compound 16 was replacedwith  

¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.25 (m, 9H), 7.24- 7.12 (m, 2H),7.08-6.92 (m, 4H), 4.37 (s, 1H), 4.22 (s, 2H), 4.05-3.95 (m, 2H), 3.50(d, J = 11.2 Hz, 1H), 3.26 (d, J = 12.8 Hz, 1H), 2.59 (s, 3H), 1.90-1.70(m, 2H), 1.55- 1.25 (m, 2H). MS m/z (ESI): 534.6 [M + H]⁺. The reactionin step 5a did not take place. C260

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl (furan-3-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. 1H NMR (400 MHz, DMSO-d₆)δ 13.02 (s, 1H), 7.60-7.56 (m, 2H), 7.35 (t, J = 7.9 Hz, 4H), 7.17 (t, J= 7.4 Hz, 2H), 7.01 (d, J = 7.6 Hz, 4H), 6.35 (s, 1H), 4.35-4.20 (m,3H), 4.07 (d, J = 15.4 Hz, 1H), 3.88 (s, 1H), 3.42 (s, 1H), 3.36 (s,1H), 3.22-3.14 (m, 1H), 3.05-2.95 (m, 1H), 1.68 (s, 1H), 1.53 (s, 1H),1.30 (d, J = 42.4 Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 503.1[M + H]⁺. C225

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (1-phenylethyl)carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H),7.48-7.30 (m, 6H), 7.30- 7.20 (m, 3H), 7.17 (t, J = 8.0 Hz, 2H), 7.01(d, J = 8.0 Hz, 4H), 5.24-5.16 (m, 1H), 4.41- 4.28 (m, 2H), 3.40-3.80(m, 1H), 3.50-3.39 (m, 2H), 2.53 (s, 1H), 2.43 (s, 1H), 1.76 (s, 1H),1.58 (s, 1H), 1.49-1.39 (m, 3H), 1.33-1.16 (m, 2H). MS m/z (ESI): 513.1[M + H]⁺. did not take place. C229

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (1-(thiophene- 3-yl)ethyl)carbamoyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.03 (s, 1H), 7.53-7.47 (m, 1H), 7.45- 7.28 (m, 5H), 7.25-7.15 (m,2H), 7.10-6.98 (m, 4H), 6.97- 6.88 (m, 1H), 5.20-5.05 (m, 1H), 4.40-4.15(m, 2H), 3.89 (d, J = 22.4 Hz, 1H), 3.45- 3.35 (m, 2H), 2.50-2.40 (m,3H), 1.80-1.48 (m, 2H), 1.48- 1.27 (m, 5H). MS m/z (ESI): 541.0 [M +Na]⁺. C215

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(Methyl(4- (prop-1-ene-2-yl)benzyl)) carbamoyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylicacid Compound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.47 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 8.0 Hz, 4H), 7.20-7.10 (m, 4H),7.01 (d, J = 7.6 Hz, 4H), 5.42 (s, 1H), 5.08 (s, 1H), 4.42 (d, J = 15.2Hz, 1H), 4.40-4.28 (m, 2H), 4.27 (d, J = 15.6 Hz, 1H), 3.93 (s, 1H),3.45-3.34 (m, 2H), 2.70 (s, 3H), 2.10 (s, 3H), 1.80-1.65 (m, 1H), 1.62-1.50 (m, 1H), 1.45-1.20 (m, 1H). MS m/z (ESI): 539.0 [M + H]⁺. C200

(1R,2S,5S)-8- (cyclopropyl (thiophene-2-ylmethyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 7.47-7.34 (m, 3H), 7.22 (d, J= 8.4 Hz, 3H), 7.03-6.95 (m, 1H), 4.59 (s, 1H), 4.27 (s, 1H), 4.15-4.05(m, 1H), 3.20- 3.09 (m, 1H), 2.55 (s, 1H), 1.92-1.80 (m, 1H), 1.52 (s,2H), 0.76-0.64 (m, 2H). MS m/z (ESI): 531.1 [M + H]⁺. The reaction instep 5a did not take place. C265

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (quinoline-2-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.15 (d, J =7.6 Hz, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.61(d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.6 Hz, 2H),7.02 (d, J = 7.2 Hz, 4H), 4.86 (d, J = 16.4 Hz, 1H), 4.66 (d, J = 16.4Hz, 1H), 4.44-4.20 (m, 2H), 4.09 (s, 1H), 3.50- 3.30 (m, 2H), 2.97 (s,3H), 1.75-1.20 (m, 4H). MS m/z (ESI): 549.8 [M + H]⁺. in step 5a did nottake place. C266

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (quinoline-6-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.64 (s, 1H),8.10 (d, J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.36(t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H), 7.01 (d, J = 7.2 Hz, 4H),4.68 (d, J = 16.0 Hz, 1H), 4.48 (d, J = 16.0 Hz, 1H), 4.44-4.25 (m, 2H),3.99 (s, 1H), 3.48-3.32 (m, 2H), 2.79 (s, 3H), 1.79-1.20 (m, 4H). MS m/z(ESI): 549.8 [M + H]⁺. in step 5a did not take place. C187

(1R,2S,5S)-3- (2,2-diphenylacetyl)- 8-(methyl(thiophene- 3-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound16 in step 5b of Example 5 was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 7.50-6.95 (m,13H), 5.50-5.35 (m, 1H), 4.80-4.00 (m, 5H), 4.00- 3.50 (m, 2H),2.80-2.60 (m, 3H), 1.80-1.00 (m, 4H). MS m/z (ESI): 504.1 [M + H]⁺. didnot take place. C237

(1R,2S,5S)-8- ((4-(tert-butyl)benzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.45-6.89 (m, 14H), 4.40 (d,J = 15.2 Hz, 2H), 4.22 (d, J = 15.2 Hz, 1H), 3.94 (s, 1H), 3.42 (d, J =12.5 Hz, 2H), 2.71 (s, 3H), 1.69 (s, 1H), 1.57 (s, 1H), 1.41 (d, J = 6.1Hz, 1H), 1.25 (s, 9H), 1.21-1.07 (m, 1H). MS m/z (ESI): 554.7 [M + H]⁺.The reaction in step 5a did not take place. C148

(1R,2S,5S)-8- ((cyclohexylmethyl) (cyclopropyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 12.93 (s, 1H), 7.36 (t, J = 7.9 Hz, 4H), 7.17 (t, J = 7.4 Hz, 2H),7.02 (d, J = 7.6 Hz, 4H), 4.48-4.18 (m, 2H), 4.08 (s, 1H), 3.34 (dd, J =13.4, 8.7 Hz, 1H), 2.68 (dd, J = 13.4, 5.5 Hz, 1H), 2.58 (s, 1H),1.73-1.48 (m, 7H), 1.42 (s, 2H), 1.29-1.05 (m, 4H), 0.92-0.67 (m, 3H),0.65- 0.57 (m, 1H), 0.55-0.40 (m, 2H). MS m/z (ESI): 530.7 [M + H]⁺.C201

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl(thiophene-2-ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, CD₃OD) δ7.40-7.33 (m, 4H), 7.30 (dd, J = 5.2, 1.2 Hz, 1H), 7.24- 7.18 (m, 2H),7.15-7.05 (m, 4H), 7.00-6.92 (m, 2H), 4.70 (d, J = 15.6 Hz, 1H), 4.58-4.45 (m, 3H), 3.99 (s, 1H), 3.58-3.45 (m, 2H), 3.40- 3.34 (m, 1H),3.23-3.14 (m, 1H), 1.95-1.53 (m, 4H), 1.11 (t, J = 7.2 Hz, 3H). MS m/z(ESI): 518.8 [M + H]⁺. C245

(1R,2S,5S)-8- ((benzo[b]thiophene- 3-ylmethyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.04 (s, 1H), 8.02-7.95 (m, 1H), 7.69 (dd, J = 6.1, 2.8 Hz, 1H), 7.60(s, 1H), 7.44-7.31 (m, 6H), 7.16 (t, J = 7.4 Hz, 2H), 7.01 (d, J = 7.5Hz, 4H), 4.82 (d, J = 15.4 Hz, 1H), 4.44 (d, J = 15.4 Hz, 1H), 4.41-4.27(m, 2H), 3.88 (s, 1H), 3.38 (dd, J = 29.8, 12.4 Hz, 2H), 3.29- 3.18 (m,1H), 3.03-2.91 (m, 1H), 1.83-1.68 (m, 1H), 1.63- 1.50 (m, 1H), 1.46-1.31(m, 1H), 1.24 (s, 1H), 0.98 (t, J = 7.0 Hz, 3H) . MS m/z (ESI): 569.1[M + H]⁺. C246

(1R,2S,5S)-8-(benzo [b]thiophene- 3-ylmethyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.97 (m, 1H),7.72-7.65 (m, 1H), 7.60 (s, 1H), 7.40-7.30 (m, 6H), 7.16 (t, J = 7.2 Hz,2H), 7.00 (d, J = 6.0 Hz, 4H), 4.82 (d, J = 15.0 Hz, 1H), 4.44 (d, J =15.1 Hz, 1H), 4.39 (s, 1H), 3.84 (s, 1H), 3.43-3.35 (m, 2H), 2.72 (s,3H), 1.77 (s, 1H), 1.54 (s, 1H), 1.33 (d, J = 14.4 Hz, 1H), 1.31-1.24(m, 1H). MS m/z (ESI): 555.0 [M + H]⁺. did not take place. C156

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl(2- fluorobenzyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.04 (s, 1H), 7.43-7.32 (m, 4H), 7.31- 7.2 (m, 2H), 7.21-7.11 (m,4H), 7.01 (d, J = 7.6 Hz, 4H), 4.57 (d, J = 15.6 Hz, 1H), 4.31 (s, 1H),4.25 (d, J = 15.6 Hz, 1H), 3.89 (s, 1H), 3.43 (d, J = 12.0 Hz, 1H), 3.35(d, J = 12.2 Hz, 1H), 3.29-3.21 (m, 1H), 3.05-2.96 (m, 1H), 2.49- 2.44(m, 1H), 1.66 (s, 1H), 1.52 (s, 1H), 1.44-1.17 (m, 2H), 1.00 (t, J = 6.8Hz, 3H). MS m/z (ESI): 531.1 [M + H]⁺. C198

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((1- methylcyclopropyl(thiophene-3- ylmethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2-carboxylic acid Compound 20 in step 5b of Example 5 was replaced withCompound 23. Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.05 (s, 1H), 7.50-7.44 (m, 1H), 7.35 (t, J = 8.0 Hz, 4H), 7.28 (d, J= 2.0 Hz, 1H), 7.23-7.13 (m, 2H), 7.01 (d, J = 7.6 Hz, 4H), 6.96 (d, J =4.6 Hz, 1H), 4.55 (d, J = 15.2 Hz, 1H), 4.44-4.25 (m, 2H), 4.19 (d, J =15.2 Hz, 1H), 3.94 (s, 1H), 3.42-3.36 (m, 2H), 1.70-1.20 (m, 4H), 0.97(s, 3H), 0.75-0.65 (m, 2H), 0.59-0.56 (m, 1H), 0.48- 0.44 (m, 1H). MSm/z (ESI): 545.1 [M + H]⁺. C114

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-((2-fluorobenzyl)(methyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a 1H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1H),7.37-7.33 (m, 4H), 7.33- 7.21 (m, 2H), 7.21-7.19 (m, 4H), 7.01 (d, J =7.6 Hz, 4H), 4.56 (d, J = 15.6 Hz, 1H), 4.34 (s, 1H), 4.27 (d, J = 15.6Hz, 1H), 3.90 (s, 1H), 3.46- 3.35 (m, 2H), 3.33-3.27 (m, 1H), 2.75 (s,3H), 1.69 (s, 1H), 1.53 (s, 1H), 1.30 (d, J = 47.7 Hz, 2H). MS m/z(ESI): 517.2 [M + H]⁺. did not take place. C142

(1R,2S,5S)-8-((S)-2- (2,5-difluorophenyl) pyrrolidine- 1-carbonyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 7.43-6.94 (m, 13H), 5.01 (t,J = 7.8 Hz, 1H), 4.56 (s, 1H), 4.32-4.06 (m, 1H), 4.00 (s, 1H),3.72-3.60 (m, 1H), 3.52 (t, J = 7.2 Hz, 1H), 3.41 (d, J = 11.4 Hz, 1H),3.24 (d. J = 11.7 Hz. 1H). 2.33- 2.19 (m, 1H), 1.91-1.71 (m, 2H),1.59-1.16 (m, 5H) . MS m/z (ESI): 560.7 [M + H]⁺. The reaction in step5a did not take place. C141

(1R,2S,5S)-8-((R)-2- (2,5-difluorophenyl) pyrrolidine-1- carbonyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 7.44-6.95 (m, 13H), 5.01 (t,J = 7.8 Hz, 1H), 4.56 (s, 1H), 4.32-4.09 (m, 1H), 4.00 (s, 1H),3.71-3.58 (m, 1H), 3.57- 3.48 (m, 1H), 3.41 (d, J = 11.4 Hz, 1H), 3.24(d, J = 11.7 Hz, 1H), 2.35-2.21 (m, 1H), 1.91-1.72 (m, 2H), 1.62- 1.11(m, 5H). MS m/z (ESI): 560.7 [M + H]⁺. The reaction in step 5a did nottake place. C202

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl((5- methylthiophen-2-yl)methyl) carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylicacid Compound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.35 (t, J = 7.6 Hz, 4H), 7.16 (t, J = 7.2 Hz, 2H), 7.01 (d, J = 8.0Hz, 4H), 6.75 (s, 1H), 6.60 (s, 1H), 4.51- 4.42 (m, 1H), 4.37-4.10 (m,3H), 3.88 (s, 1H), 3.44 (d, J = 12.0 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H),3.29-3.13 (m, 1H), 3.09-2.98 (m, 1H), 2.37 (s, 3H), 1.74-1.21 (m, 4H),1.01 (t, J = 6.8 Hz, 3H). MS m/z (ESI): 533.1 [M + H]⁺. C249

(1R,2S,5S)-8- (((1H-indole-6-yl) methyl)(methyl) carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 7.48 (d, J =8.4 Hz, 1H), 7.41- 7.28 (m, 5H), 7.23 (s, 1H), 7.17 (t, J = 7.2 Hz, 2H),7.01 (d, J = 7.6 Hz, 4H), 6.83 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 4.51(d, J = 14.8 Hz, 1H), 4.35 (d, J = 14.8 Hz, 3H), 3.91 (s, 1H), 2.72-2.66(m, 3H), 1.76 (s, 1H), 1.57 (s, 2H), 1.39 (s, 1H). MS m/z (ESI): 537.7[M + H]⁺. in step 5a did not take place. C204

(1R,2S,5S)-8- (cyclopropyl(5- methylthiophen-2-yl) methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction 1H NMR (400 MHz, DMSO-d₆) δ 13.00 (s, 1H), 7.36 (t, J =7.6 Hz, 4H), 7.21- 7.11 (m, 2H), 7.02 (d, J = 8.0 Hz, 4H), 6.79-6.69 (m,1H), 6.62 (s, 1H), 4.72 (d, J = 15.2 Hz, 1H), 4.52-4.22 (s, 2H),4.19-4.04 (m, 2H), 3.93- 3.59 (m, 2H), 2.38 (s, 4H), 1.69 (s, 1H), 1.49(s, 3H), 0.74 (s, 1H), 0.61 (d, J = 5.2 Hz, 2H), 0.53 (s, 1H). MS m/z(ESI): 545.1 [M + H]⁺. in step 5a did not take place. C252

(1R,2S,5S)-8- (((2,3-dihydrobenzo [b][1,4]dioxin- 6-yl)methyl)(methyl)carbamoyl)-3- (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 20 in step 5b of Example 5 wasreplaced with Compound 23. Compound 16 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H), (t, J = 7.4Hz, 2H), 7.01 (d, J = 7.9 Hz, 4H), 6.79 (d, J = 8.1 Hz, 1H), 6.72-6.57(m, 2H), 4.35 (s, 1H), 4.28 (d, J = 15.0 Hz, 2H), 4.21 (s, 4H), 4.15 (d,J = 14.9 Hz, 1H), 3.90 (s, 1H), 3.39 (dd, J = 30.2, 12.1 Hz, 2H), 2.67(s, 3H), 1.73 (s, 1H), 1.54 (s, 1H), 1.40 (s, 1H), 1.28-1.16 (m, 1H). MSm/z (ESI): 556.6 [M + H]⁺. in step 5a did not take place. C226

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl((R)-1- phenylethyl)carbamoyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.31 (m, 6H), 7.29-7.21 (m, 3H), 7.20-7.14 (m, 2H), 7.03-7.00 (m, 4H), 5.21-5.15 (m, 1H), 4.37- 4.25 (m, 2H),3.86 (s, 1H), 3.46-3.36 (m, 2H), 2.43 (s, 3H), 1.80-1.51 (m, 3H), 1.46(d, J = 7.2 Hz, 3H), 1.40- 1.30 (m, 1H). MS m/z (ESI): 513.2 [M + H]⁺.The reaction in step 5a did not take place. C227

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl ((S)-1-phenylethyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.00 (s, 1H), 7.39-7.32 (m, 6H), 7.29- 7.23(m, 3H), 7.20-7.14 (m, 2H), 7.01 (d, J = 7.6 Hz, 4H), 5.27-5.19 (m, 1H),4.32 (s, 2H), 3.93 (s, 1H), 3.46-3.36 (m, 2H), 2.55 (d, J = 14.2 Hz,3H), 1.71 (s, 1H), 1.65-1.53 (m, 1H), 1.53-1.26 (m, 5H). MS m/z (ESI):513.1 [M + H]⁺. The reaction in step 5a did not take place. C203

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl ((5-methylthiophen-2-yl)methyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (t, J = 7.6 Hz, 4H), 7.17 (t, J = 7.6Hz, 2H), 7.01 (d, J = 7.6 Hz, 4H), 6.76 (d, J = 3.2 Hz, 1H), 6.63- 6.15(m, 1H), 4.43-4.31 (m, 4H), 3.89 (s, 1H), 3.44-3.32 (m, 2H), 2.73 (s,3H), 2.38 (s, 3H), 1.75-1.30 (m, 4H). MS m/z (ESI): 518.8 [M + H]⁺. Thereaction in step 5a did not take place. C185

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (5-methylthiophen-3-yl)methyl) carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylicacid Compound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.2Hz, 2H), 7.05-6.96 (m, 5H), 6.64 (s, 1H), 4.39-4.23 (m, 3H), 4.15 (d, J= 14.8 Hz, 1H), 3.91 (s, 1H), 3.45-3.35 (m, 2H), 2.70 (s, 3H), 2.40 (s3H), 1.80-1.45 (m, 4H). MS m/z (ESI): 519.1 [M + H]⁺. The reaction instep 5a did not take place. C186

(1R,2S,5S)-8- (((5-chlorothiophene- 3-yl)methyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.15 (s, 1H), 7.35 (t, J = 7.6 Hz, 4H), 7.22 (s, 1H), 7.16 (t, J =7.2 Hz, 2H), 7.02 (d, J = 7.6 Hz, 4H), 6.95 (d, J = 1.6 Hz, 1H), 4.36(s, 1H) 4.28 (d, J = 15.2 Hz, 2H), 4.22-4.11 (m, 1H), 3.93 (s, 1H),3.50-3.36 (m, 2H), 2.73 (s, 3H), 1.67 (s, 1H), 1.60- 1.50 (m, 1H),1.46-1.23 (m, 2H). MS m/z (ESI): 539.0 [M + H]⁺. C208

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl((5- methylthiophen-3-yl)methyl) carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylicacid Compound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.36 (t, J = 7.2 Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H), 7.03-7.00 (m, 5H),6.63 (s, 1H), 4.36-4.20 (m, 3H), 4.13 (d, J = 15.6 Hz, 1H), 3.88 (s,1H), 3.45-3.30 (m, 2H), 3.21-3.15 (m, 1H), 3.02- 2.96 (m, 1H), 2.40 (s,3H), 1.70-1.49 (m, 2H), 1.45- 1.24 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). MSm/z (ESI): 532.8 [M + H]⁺. C274

(1R,2S,5S)-8- (((5-chlorothiophene- 3-yl)methyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz DMSO-d₆) δ13.10 (s, 1H), 7.35 (t, J = 8.0 Hz, 4H), 7.21 (d, J = 1.2 Hz, 1H), 7.16(t, J = 7.2 Hz, 2H), 7.02 (d, J = 7.6 Hz, 4H), 6.94 (d, J = 1.6 Hz, 1H),4.34 (d, J = 15.6 Hz, 2H), 4.16 (d, J = 15.6 Hz, 1H), 3.90 (s, 1H),3.45-3.35 (m, 2H), 3.25-3.15 (m, 1H), 3.07-2.98 (m, 1H), 1.66 (s, 1H),1.55 (s, 1H), 1.45-1.19 (m, 2H), 0.99 (t, J = 7.0 Hz, 3H). MS m/z (ESI):552.7 [M + H]⁺. C271

(1R,2S,5S)-8- (benzo[b]thiophene- 2-ylmethyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1 H), 7.90 (d, J =7.6 Hz, 1H), 7.81- 7.75 (m, 1H), 7.39-7.29 (m, 7H), 7.17 (t, J = 7.2 Hz,2H), 7.02 (d, J = 7.2 Hz, 4H), 4.65 (d, J = 15.6 Hz, 1H), 4.54 (d, J =15.6 Hz, 1H), 4.45-4.20 (m, 2H), 3.96 (s, 1H), 3.50- 3.33 (m, 2H), 2.83(s, 3H), 1.80-1.30 (m, 4H). MS m/z (ESI): 555.1 [M + H]⁺. in step 5a didnot take place. C273

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl((4- methylthiophen-2-yl)methyl) carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 7.35 (t, J = 8.0 Hz, 4H), 7.16 (t, J = 7.2 Hz, 2H), 7.07-6.90 (m, 5H),6.79 (s, 1H), 4.52 (d, J = 15.6 Hz, 1H), 4.35 (d, J = 15.6 Hz, 2H), 3.88(s, 1H), 3.44 (d, J = 12.8 Hz, 1H), 3.34 (d, J = 12.0 Hz, 2H), 3.25-3.16(m, 1H), 3.11-3.02 (m, 1H), 2.18- 2.11 (m, 3H), 1.67 (s, 1H), 1.55 (s,1H), 1.49-1.24 (m, 2H), 1.02 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 532.9[M + H]⁺. C272

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(ethyl((3- methylthiophen-2-yl)methyl) carbamoyl)-3, 8-diazabicyclo [3.2.1]octane-2- carboxylicacid Compound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.02 (s, 1H), 7.36 (t, J = 7.6 Hz, 4H), 7.28 (d, J = 5.2 Hz, 1H),7.17 (t, J = 7.2 Hz, 2H), 6.99 (d, J = 7.6 Hz, 4H), 6.81 (t, J = 8.0 Hz,1H), 4.57 (d, J = 15.6 Hz, 1H), 4.42-4.16 (m, 3H), 3.88 (s, 1H), 3.45(d, J = 12.0 Hz, 1H), 3.36 (s, 1H), 3.27-3.16 (m, 1H), 3.07-2.96 (m,1H), 2.16-2.08 (m, 3H), 1.70 (s, 1H), 1.54 (s, 1H), 1.45-1.20 (m, 2H),1.04-0.96 (m, 3H). MS m/z (ESI): 533.2 [M + H]⁺. C197

(1R,2S,5S)-8- (cyclopropyl(5- methylthiophen-3- yl)methyl)carbamoyl)- 3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 12.96 (s, 1H), 7.36 (t, J = 8.0 Hz, 4H), 7.17 (t, J = 7.2 Hz, 2H),7.02 (d, J = 7.6 Hz, 4H), 6.98 (s, 1H), 6.62 (s, 1H), 4.52 (d, J = 15.2Hz, 1H), 4.46 (s, 1H), 4.38- 4.21 (m, 1H), 4.17-4.05 (m, 1H), 3.96 (d, J= 14.8 Hz, 1H), 3.45-3.35 (m, 2H), 2.45- 2.35 (m, 4H), 1.75-1.20 (m,4H), 0.75-0.40 (m, 4H). MS m/z (ESI): 544.6 [M + H]⁺. C281

(1R,2S,5S)-8- (((5-chlorothiophene- 2-yl)methyl) (ethyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1] octane-2- carboxylic acidCompound 20 in step 5b of Example 5 was replaced with Compound 23.Compound 16 was replaced with  

  The reaction in step 5a did not take place. ¹H NMR (400 MHz, DMSO-d₆)δ 13.07 (s, 1H), 7.35 (t, J = 7.6 Hz, 4H), 7.17 (t, J = 7.6 Hz, 2H),7.02 (d, J = 7.6 Hz, 4H), 6.93 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 4.0 Hz,1H), 4.43 (d, J = 15.6 Hz, 1H), 4.37-4.20 (m, 3H), 3.90 (s, 1H), 3.45(d, J = 11.6 Hz, 1H), 3.36 (s, 1H), 3.25-3.15 (m, 6.7 Hz, 1H), 3.12-3.04(m, 1H), 1.65 (s, 1H), 1.55 (s, 1H), 1.41 (s, 2H), 1.03 (t, J 7.0 Hz,3H). MS m/z (ESI): 553.2 [M + H]⁺. C163

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(methyl (2-methylbenzyl)carbamoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5b of Example 5 was replaced with Compound 23. Compound 16was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.51-6.86 (m, 14H), 4.50-4.20 (m, 4H), 3.91(s, 1H), 3.51-3.45 (m, 1H), 2.71 (s, 3H), 2.16 (s, 3H), 1.70-1.10 (m,4H). MS m/z (ESI): 513.1 [M + H]⁺. The reaction in step 5a did not takeplace. C119

(1R,2S,5S)-8- ((benzyloxy)carbonyl)- 3-(1- phenylcyclohexane-1-carbonyl)-3,8- diazabicyclo [3.2.1]octane-2- carboxylic acid Compound7 in step 3 of Example 5 was replaced with  

  Phenyl chloroformate in step 5a was replaced with benzyl ¹H NMR (400Hz, DMSO-d₆) δ 7.40-7.24 (m, 10H), 5.03 (d, J = 13.2 Hz, 1H), 5.00-4.80(m, 1H), 4.72 (s, 1H), 4.64 (d, J = 6.0 Hz, 1H), 3.92 (s, 1H), 3.19 (d,J = 12.0 Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.36-2.25 (m, 2H),1.86-1.29 (m, 12H). MS m/z (ESI): 477.2 [M + H]⁺. chloroformate. Thereaction in step 5b did not take place. C120

(1R,2S,5S)-8- (benzyl(methyl) carbamoyl)-3-(1- phenylcyclohexane-1-carbonyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound7 in step 3 of Example 5 was replaced with  

  The reaction in step 5a ¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.23 (m, 8H),7.14 (d, J = 7.2 Hz, 2H), 4.84 (s, 1H), 4.45-4.36 (m, 2H), 4.25-4.15 (m,1H), 3.62 (s, 1H), 3.30- 3.10 (m, 2H), 2.64 (s, 3H), 2.35- 2.20 (m, 2H),1.85-1.70 (m, 3H), 1.69-1.47 (m, 5H), 1.40- 1.20 (m, 4H). MS m/z (ESI):490.1 [M + H]⁺. did not take place. C122

(1R,2S,5S)-8- (phenylcarbamoyl)- 3-(1- phenylcyclohexane-1-carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acid Compound 7in step 3 of Example 5 was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (brs, 1H), 7.46-7.14 (m, 9H), 6.95-6.85(s, 1H), 4.89 (d, J = 6.4 Hz, 1H), 4.74 (s, 1H), 4.06 (s, 1H), 3.2-3.05(m, 2H), 2.35-2.20 (m, 2H), 1.90- 1.50 (m, 8H), 1.50-1.33 (m, 2H),1.3-1.15 (m, 2H). MS m/z (ESI): 462.1 [M + H]⁺. Compound 16 in step 5bwas replaced with phenylamine. The reaction in step 5a did not takeplace. C37

(1R,2S,5S)-8- ((benzyloxy)carbonyl)- 3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with benzyl chloroformate. The reaction in step 5b did not takeplace. ¹H NMR (400 MHz, DMSO-d₆) δ 13.03 (s, 1H), 7.40-7.26 (m, 8H),7.17 (t, J = 7.4 Hz, 2H), 7.01 (d, J = 7.5 Hz, 4H), 5.08 (d, J = 12.8Hz, 1H), 4.98 (s, 1H), 4.58 (s, 1H), 4.25 (d, J = 22.0 Hz, 2H), 3.44 (d,J = 12.1 Hz, 1H), 3.27 (d, J = 10.9 Hz, 1H), 1.77-1.62 (m, 2H), 1.45-1.23 (m, 2H). MS m/z (ESI): 486.0 [M + H]⁺. C174

(1R,2S,5S)-8- cinnamoyl-3- (diphenylcarbamoyl)- 3,8-diazabicyclo[3.2.1]octane- 2-carboxylic acid Compound 20 in step 5a of Example 5 wasreplaced with Compound 23. The phenyl chloroformate was replaced withcinnamoyl chloride. The reaction in step 5b did not take place. ¹H NMR(400 MHz, DMSO-d₆) δ 13.27 (s, 1H), 7.67 (d, J = 16.8 Hz, 2H), 7.52-7.29(m, 7H) 7.18 (t, J = 7.4 Hz, 2H), 7.02, (d, J = 7.6 Hz, 4H), 5.03 (d, J= 28.3 Hz, 1H), 4.66 (d, J = 47.4 Hz, 1H), 4.35 (s, 1H), 3.47 (s, 1H),3.19 (s, 1H), 1.93- 1.62 (m, 2H), 1.58-1.35 (m, 2H). MS m/z (ESI): 481.8[M + H]⁺. C193

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(((4-methylbenzyl)oxy)carbonyl)-3,8- diazabicyclo[3.2.1] octane-2- carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23,phenyl chloroformate was replaced with  

  And the ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (brs, 1H), 7.36 (t, J = 8.0Hz, 4H), 7.24-7.12 (m, 6H), 7.00 (d, J = 7.6 Hz, 4H), 5.05-4.85 (m, 2H),4.57 (d, J = 5.6 Hz, 1H), 4.25 (s, 1H), 4.20 (s, 1H), 3.43 (d, J = 11.6Hz, 1H), 3.26 (d, J = 11.2 Hz, 1H), 2.29 (s, 3H), 1.80-1.58 (m, 2H),1.45-1.25 (m, 2H). MS m/z (ESI): 499.8 [M + H]⁺. reaction condition waschanged to reacting at room temperature for 16 hours. The reaction instep 5b did not take place. C221

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3- phenylpropionyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5a ofExample 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with phenyl propionyl chloride. The reaction in step 5b did nottake 1H NMR (400 MHz, DMSO-d₆) δ 7.35 (t, J = 8.0 Hz, 4H), 7.30- 7.14(m, 7H), 7.00 (t, J = 7.2 Hz, 4H), 4.90-4.30 (m, 2H), 4.25 (s, 1H),3.45-3.25 (m, 2H), 3.05 (d, J = 12 Hz, 1H), 2.75 (t, J = 8.0 Hz, 2H),2.65- 2.30 (m, 2H), 1.60-1.40 (m, 2H), 1.39-1.20 (m, 2H). place. MS m/z(ESI): 484.1 [M + H]⁺. C238

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4-phenyl- 1H-iminazole-5-carbonyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5a of Example 5 was replaced with Compound 23. The phenylchloroformate was replaced with  

¹H NMR (400 MHz, CDCl₃) δ 7.74-6.82 (m, 15H), 4.64 (s, 1H), 4.27 (s,1H), 4.05 (s, 1H), 3.66 (s, 1H), 3.50 (d, J = 9.1 Hz, 1H), 1.71 (s, 1H),1.45 (s, 1H), 1.22 (s, 1H), 0.95-0.75 (m, 1H). MS m/z (ESI): 522.0 [M +H]⁺. The reaction in step 5b did not take place. C240

(1R,2S,5S)-8- ([1,1′-biphenyl]- 2-carbonyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 7.60-7.05 (m, 15H), 6.92 (d,J = 7.7 Hz, 4H), 4.81 (s, 1H), 4.46 (s, 1H), 4.21 (s, 1H), 3.96 (s, 1H),3.58 (s, 1H), 1.24 (m, 2H), 0.89 (m, 2H). MS m/z (ESI): 531.8 [M + H]⁺.The reaction in step 5b did not take place. C239

(1R,2S,5S)-8- (2-(4-bromophenyl) cyclopropane- 1-carbonyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23, thephenyl chloroformate was replaced with  

¹H NMR (400 MHz DMSO-d₆) δ 7.50-7.00 (m, 14H), 5.00- 4.75 (m, 1H),4.70-4.20 (m, 2H), 3.40-3.00 (m, 2H), 2.30- 2.00 (m, 2H), 1.75-1.50 (m,2H), 1.49-1.00 (m, 4H). MS m/z (ESI): 575.7 [M + H]⁺. and the reactioncondition was changed to reacting at room temperature for 12 hours. C259

(1R,2S,5S)-8- (2-(1H-indole-3- yl)acetyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 7.58-7.25 (m, 6H), 7.26-7.11(m, 3H), 7.11- 6.84 (m, 6H), 4.83 (d, J = 39.7 Hz, 1H), 4.45 (d, J =38.5 Hz, 1H), 4.23 (s, 1H), 3.77 (d, J = 49.0 Hz, 1H), 3.64 (s, 1H),3.53- 3.42 (m, 1H), 3.11 (d, J = 12.9 Hz, 1H), 1.50 (s, 2H), 1.35 (s,2H). MS m/z (ESI): 509.1 [M + H]⁺. The reaction in step 5b did not takeplace. C224

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3-phenylbutylyl)- 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid Compound 20 in step 5a of Example 5 wasreplaced with Compound 23. The phenyl chloroformate was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.30 (m, 4H), 7.29- 7.21 (m, 3H),7.20-7.11 (m, 4H), 7.01 (dd, J = 7.8, 7.6 Hz, 4H), 4.83 (s, 1H),4.53-4.09 (m, 2H), 3.39 (s, 1H), 3.15- 2.99 (m, 2H), 2.72-2.56 (m, 1H),2.42-2.30 (m, 1H), 1.61 (s, 1H), 1.39 (s, 1H), 1.31-1.21 (m, 2H),1.21-1.13 (m, 3H). MS m/z (ESI): 498.1 [M + H]⁺. The reaction in step 5bdid not take place. C264

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4-oxo- 4H-benzopyran-2-carbonyl)-3,8- diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5a of Example 5 was replaced with Compound 23. The phenylchloroformate was replaced with  

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J = 6.8 Hz, 1H), 7.90- 7.77 (m, 1H),7.61-7.51 (m, 1H), 7.50-7.30 (m, 5H), 7.28- 7.18 (m, 2H), 7.11 (t, J =8.4, 8.8 Hz, 4H), 5.21 (s, 1H), 4.57 (d, J = 48.4 Hz, 2H), 3.62 (dd, J =47.1, 27.4 Hz, 3H), 1.97 (s, 1H), 1.72 (s, 3H). MS m/z (ESI): 524.0 [M +H ]⁺. The reaction in step 5b did not take place. C256

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(3- phenylpropioloyl)-3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 7.70-6.98 (m, 15H), 4.93-4.85 (m, 1H), 4.63-4.49 (m, 1H), 4.38 (d, J = 35.6 Hz, 1H), 3.41 (d, J =10.4 Hz, 1H), 3.28-3.16 (m, 1H), 1.96- 1.85 (m, 1H), 1.84-1.75 (m, MSm/z (ESI): 480.1 [M + H]⁺. The reaction in step 5b did not take place.C257

(1R,2S,5S)-8- (3-(4-chlorophenyl) propioloyl)-3- (diphenylcarbamoyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 7.72-7.50 (m, 4H), 7.35 (t, J= 7.6, 8.0 Hz, 4H), 7.21 (t, J = 7.6, 7.2 Hz, 2H), 7.01 (d, J = 8.0 Hz,4H), 4.92-4.85 (m, 1H), 4.60-4.50 (m, 1H), 4.45-4.30 (m, 1H), 3.45-3.32(m, 1H), 3.23 (d, J = 24.0 Hz, 1H), 1.90-1.62 (m, 2H), 1.44 (s, 2H). MSm/z (ESI): 514.0 [M + H]⁺. The reaction in step 5b did not take place.C35

(1R,2S,5S)-3- (2,2-diphenylacetyl)- 8-(((2-fluorobenzyl) oxy)carbonyl)-3,8-diazabicyclo [3.2.1]octane-2- carboxylic acid Compound 20 in step 5aof Example 5 was replaced with Compound 23. The phenyl chloroformate wasreplaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.05 (m, 14H), 5.55- 5.30 (m, 1H),5.20-4.60 (m, 2H), 4.30-4.00 (m, 2H), 3.71- 3.50 (m, 1H), 3.45-3.37 (m,2H), 1.90-1.00 (m, 4H). MS m/z (ESI): 502.8 [M + H]⁺. The reaction instep 5b did not take place. C241

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(2-(1- methyl-1H-pyrazole-4-yl)benzoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23. Thephenyl chloroformate was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.65 (m, 1H), 7.55-7.45 (m, 2H),7.44-7.36 (m, 1H), 7.35-7.22 (m, 5H), 7.19-7.08 (m, 3H), 6.95 (d, J =8.0 Hz, 4H), 4.99 (s, 1H), 4.63 (s, 1H), 4.27 (s, 1H), 3.83 (s, 3H),3.30- 3.14 (m, 2H), 1.65-0.95 (m, 4H). MS m/z (ESI): 536.1 [M + H]⁺. Thereaction in step 5b did not take place. C36

(1R,2S,5S)-8- (((2,6-diflurorbenzyl) oxy)carbonyl)-3-(2,2-diphenylacetyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23. Thephenyl chloroformate was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 13.00-12.50 (m, 1H), 7.55- 7.41 (m, 1H),7.40-7.06 (m, 12H), 5.51-5.29 (m, 1H), 5.20- 5.00 (m, 2H), 4.65-4.50 (m,1H), 4.27-4.00 (m, 2H), 3.73- 3.30 (m, 2H), 2.10-1.30 (m, 4H). MS m/z(ESI): 521.0 [M + H]⁺. The reaction in step 5b did not take place. C113

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(1- phenylcyclopentane-1-carbonyl)-3,8- diazabicyclo [3.2.1]octane- 2-carboxylic acid Compound20 in step 5a of Example 5 was replaced with Compound 23. The phenylchloroformate was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 7.39-7.22 (m, 6H), 7.21-7.09(m, 5H), 6.92 (d, J = 7.6 Hz, 4H), 4.94 (s, 1H), 4.18 (s, 1H), 3.72 (s,1H), 3.03 (s, 1H), 2.87 (s, 1H), 2.20 (s, 2H), 1.99 (s, 2H), 1.79-1.41(m, 6H), 1.30-1.11 (m, 2H). MS m/z (ESI): 524.1 [M + H]⁺. The reactionin step 5b did not take place. C243

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(2-(4- methylpiperazine-1-yl)benzoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23. Thephenyl chloroformate was replaced with  

¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2Hz, 4H), 7.30-7.12 (m, 5H), 7.07 (d, J = 7.6 Hz, 4H), 5.22 (s, 1H),4.80-4.25 (m, 2H), 3.62-3.36 (m, 5H), 3.28-3.06 (m, 3H), 3.05-2.97 (s,3H), 2.96-2.75 (m, 2H), 2.05-1.50 (m, 4H). MS m/z (ESI): 554.2 [M + H]⁺.The reaction in step 5b did not take place. C242

(1R,2S,5S)-3- (diphenylcarbamoyl)- 8-(4-(1- methyl-1H-pyrazole-4-yl)benzoyl)- 3,8-diazabicyclo [3.2.1]octane- 2-carboxylic acidCompound 20 in step 5a of Example 5 was replaced with Compound 23. Thephenyl chloroformate was replaced with  

¹H NMR (400 MHz, CD₃OD) δ 8.04 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.0Hz, 2H), 7.48-7.34 (m, 6H), 7.22 (t, J = 7.2 Hz, 2H), 7.10 (d, J = 7.6Hz, 4H), 4.54 (s, 2H), 3.95 (s, 3H), 3.60 (s, 2H), 2.00 (d, J = 33.5 Hz,1H), 1.89 (s, 1H), 1.62 (s, 2H). MS m/z (ESI): 535.7 [M + H]⁺. Thereaction in step 5b did not take place. C270

(1R,2S,5S)-8-((R)- 2-(dimethylamino)- 3-phenylpropionyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidC79-1 in step 6 of Example 5 was replaced with C270-1. ¹H NMR (400 MHz,CD₃OD) δ 7.41-7.25 (m, 9H), 7.24-7.16 (m, 2H), 7.05 (d, J = 7.6 Hz, 4H),4.60-4.41 (m, 3H), 4.14 (s, 1H), 3.59-3.48 (m, 2H), 3.10-2.83 (m, 8H),1.43-1.29 (m, 2H), 1.29-1.15 (m, 1H), 1.02 (s, 2H). MS m/z (ESI): 526.9[M + H]⁺. C269

(1R,2S,5S)-8-((S)- 2-(dimethylamino)- 3-phenylpropionyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidC79-1 in step 6 of Example 5 was replaced with C269-1. ¹H NMR (400 MHz,DMSO-d₆) δ 7.39-7.30 (m, 4H), 7.27-7.18 (m, 3H), 7.17- 7.10 (m, 4H),7.03 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 3H), 4.90-4.75 (m, 1H),4.55- 4.35 (m, 1H), 4.20-4.00 (m, 2H), 3.75-3.55 (m, 1H), 3.35- 3.25 (m,2H), 2.90-2.70 (m, 2H), 2.27-2.19 (m, 6H), 1.75- 0.90 (m, 4H). MS m/z(ESI): 527.1 [M + H]⁺. C167

(1R,2R,5S)-8- ((4-cyanobenzyl) (methyl)carbamoyl)-3-(diphenylcarbamoyl)- 3,8-diazabicyclo [3.2.1]octane-2- carboxylic acidCompound C82-1 in step 6 of Example 5 was replaced with C167-1. ¹H NMR(400 MHz, DMSO-d₆) δ 13.06 (s, 1H), 7.81-6.95 (m, 14H), 4.51 (s, 1H),4.43-4.28 (m, 3H), 3.95 (s, 1H), 3.46-3.36 (m, 2H), 2.75 (s, 3H),1.75-1.40 (m, 4H). MS m/z (ESI): 523.8 [M + H]⁺.

Example 6: preparation of (1R,2R,5S)-ethyl8-((4-cyanobenzyl)(methyl)carbamoyl)-3-(diphenyl-carbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate(C167-1)

Compound C165-1 (60 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide(20 mL), and Zn(CN)₂ (24 mg, 0.2 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol),dppf (56 mg, 0.1 mmol), and Zn (7 mg, 0.1 mmol) were added sequentially.The reaction solution was allowed to react for 16 horns at 100° C. undernitrogen protection. LC-MS indicated that the reaction of the startingmaterials was substantially complete. The reaction solution wasconcentrated under reduced pressure to evaporate offN,N-dimethylformamide. Saturated sodium chloride solution (10 mL) wasthen added and extracted with ethyl acetate (20 mL/2), and dried byadding anhydrous sodium sulfate (5 g) for 30 min, filtered andconcentrated under reduced pressure. The resulting crude product wassubjected to separation by preparative plate chromatography to obtainCompound C167-1 (50 mg, white solid, yield: 90%).

MS m/z (ESI): 551.8 [M+H]⁺.

Example 7: preparation of (1R,2R,5S)-ethyl8-((R)-2-(dimethylamino)-3-phenylpropanoyl)-3-(di-phenylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate(C270-1) and (1R,2R,5S)-ethyl8-((S)-2-(dimethylamino)-3-phenylpropanoyl)-3-(diphenylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (C269-1)

Compound 23 (90 mg, 0.466 mmol) was dissolved in a dichloromethanesolution (20 mL), followed by sequential addition of HATU (265 mg, 0.699mmol) and diisopropylethylamine (0.3 g, 2.33 mmol), and reaction at roomtemperature for 1 hour. Compound SM2 (88 mg, 0.233 mmol) was then addedto the reaction solution, and was reacted at 50° C. for 16 hours. Afterthe reaction was complete, 50 mL water was added to the reactionsolution, followed by extraction with dichloromethane (20 mL×2). Thecombined organic phases were dried by adding anhydrous sodium sulfate(20 g) for 30 min, filtered and concentrated under reduced pressure toobtain a crude product. The crude product was separated and purified bycolumn chromatography (petroleum ether:ethyl acetate=3:7) to obtainCompound C269-1 (90 mg, a yellow solid, crude product).

MS m/z (ESI): 555.2 [M+H]⁺.

Except replacing SM2 with SM3, by the above reaction process, CompoundC270-1 was prepared. MS m/z (ESI): 555.2 [M+H]⁺.

Example 8: preparation of(1R,2S,5S)-8-((benzyloxy)carbonyl)-3-(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C34)

Step 1:

Compound 5 (1 g, 5.04 mmol) was dissolved in a tetrahydrofuran solution(30 mL). Phenyl chloroformate (0.86 g, 5.04 mmol) and potassiumcarbonate (2.1 g, 15.13 mmol) were added sequentially, and reacted atroom temperature for 16 hours. After the reaction was complete, 50 mLwater was added to the reaction solution and extracted with ethylacetate (50 mL×2). The combined organic phases were dried by addinganhydrous sodium sulfate (100 g) for 30 min., filtered and concentratedunder reduced pressure to obtain a crude product. The crude product wasseparated and purified by column chromatography on silica gel (petroleumether:ethyl acetate=3:2) to obtain Compound 21 (1 g, a yellow oilymatter, crude product).

MS m/z (ESI): 333.1 [M+H]⁺.

Step 2:

Compound 21 (1 g, 3 mmol) was dissolved in a solution of boranedimethylsulfide in tetrahydrofuran (2M, 10 mL), purged with nitrogen for5 times, and reacted at room temperature in a nitrogen atmosphere for 3hours. After the reaction was complete, the reaction was quenched withmethanol slowly and then concentrated to obtain a crude product ofcompound 22 (0.35 g, a brownish-yellow oily liquid, crude product).

MS m/z (ESI): 319.0 [M+H]⁺.

Step 3:

Compound 22 (0.35 g, 1.1 mmol) was dissolved in dichloromethane (20 mL).To the solution, triethylamine (0.33 g, 3.3 mmol) was then added.Compound 7 (0.25 g, 1.1 mmol) was dissolved in 10 mL dichloromethane,and added dropwise to the above reaction solution and allowed to reactat room temperature for 4 horns. LC-MS indicated that the reaction ofthe starting materials was complete. It was then quenched by addingwater (30 mL), and extracted with ethyl acetate (20 mL/3). The combinedorganic phases were washed with saturated brine (20 mL×3). The organicphases were dried by adding anhydrous sodium sulfate for half an hour,and filtered. The filtrate was concentrated under reduced pressure. Theresulting crude product was subjected to separation by columnchromatography on silica gel (petroleum ether:methyl tert-butylether=1.5:1) to obtain Compound C34-1 (0.12 g, a dark yellow solid,crude product).

MS m/z (ESI): 513.0 [M+H]⁺.

Step 4:

Compound C34-1 (0.12 g, 0.234 mmol) was dissolved in a mixed solution oftetrahydrofuran, methanol and water (5 mL/5 mL/5 mL). After addingsodium hydroxide (47 mg, 1.17 mmol) and stirring at room temperature for5 horns, it was concentrated to obtain a crude product. Then, it wasadjusted to pH 5.0 with 3N hydrochloric acid solution, and extractedwith ethyl acetate (50 mL/3). The combined organic phases were washedwith saturated brine (50 mL/3). The organic phases were dried by addinganhydrous sodium sulfate for half an hour, and filtered. The filtratewas concentrated under reduced pressure, and the resulting crude productwas purified by preparative high-performance liquid chromatography(acetonitrile/water (0.1% trifluoroacetic acid solution) 40/60-20/80) toobtain Compound C34 (30 mg, a light yellow solid, yield: 26%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.00 (m, 15H), 5.50-5.30 (m, 1H),5.15-5.00 (m, 1H), 4.60 (s, 1H), 4.45-4.00 (m, 3H), 3.75-3.25 (m, 2H),2.10-1.75 (m, 2H), 1.65-1.25 (m, 2H).

MS m/z (ESI): 485.0 [M+H]⁺.

Example 9: preparation of(1S,3S,4S)-5-(benzyloxy)-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C283)

Step 1:

Compound C283-1 (10 g, 82.6 mmol) was dissolved in toluene (100 mL).Anhydrous sodium sulfate (35 g, 0.25 mol) and a 50% solution of ethylglyoxylate in toluene (16.8 g, 82.6 mmol) were added sequentially, andthe reaction solution was allowed to react at room temperature for 18hours. After filtration, the filter cake was washed with toluene (100mL), and the filtrate was concentrated under reduced pressure to removetoluene, obtaining Compound C283-2 (16 g, a colorless oily liquid,yield: 94%).

¹H NMR (400 MHz, CDCl₃): δ 7.72 (s, 1H), 7.36-7.24 (m, 5H), 4.61 (q,J=6.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.34 (t,J=7.2 Hz, 3H).

Step 2:

Compound C283-2 (16 g, 78 mmol) was dissolved in dry dichloromethane(100 mL). Under nitrogen protection, it was cooled to −15° C. to −20°C., and trifluoroacetic acid (8.3 g, 86 mmol), boron trifluorideetherate (12.2 g, 86 mmol) and 1,3-cyclohexadiene (6.9 g, 86 mmol) wereadded sequentially. The reaction solution was allowed to react at −10°C. for 2 horns. LC-MS indicated that the reaction of the startingmaterials was complete. It was then quenched by adding a saturatedNaHCO₃ solution, and extracted with dichloromethane (100 mL×3). Thecombined organic phases were washed once with saturated brine (300 mL),and then dried over anhydrous sodium sulfate for 30 min, filtered andconcentrated to obtain a crude product. The crude product was subjectedto separation by column chromatography (petroleum ether:ethylacetate=50:1 to 30:1) to obtain Compound C283-3 (7.4 g, a light yellowoily liquid, yield: 33.6%).

¹H NMR (400 MHz, CDCl₃): δ 7.42-7.31 (m, 2H), 7.27-7.16 (m, 3H),6.41-6.37 (m, 1H), 6.27-6.24 (m, 1H), 3.97 (q, J=7.2 Hz, 2H), 3.64-3.60(m, 1H), 3.43 (q, J=6.8 Hz, 1H), 2.89 (brs, 1H), 2.76-2.71 (m, 1H),2.06-2.00 (m, 1H), 1.62-1.54 (m, 1H), 1.30 (d, J=6.8 Hz, 3H), 1.31-1.24(m, 1H), 1.12 (t, J=7.2 Hz, 3H,), 1.05-0.99 (m, 1H).

MS m/z (ESI): 304.1 [M+H]⁺.

Step 3:

Compound C283-3 (4 g, 14 mmol) was dissolved in tetrahydrofuran (50 mL)and cooled to 0° C. under nitrogen protection. 1 M/L BH₃THF (15.4 mL,15.4 mmol) was slowly added dropwise. After the addition was complete,the reaction solution was stirred at room temperature for 3 hours, andthen 3N NaOH (10 mL, 30 mmol) and 30% H₂O₂ solution (20 mL) were slowlyadded dropwise at 0° C. After the addition was completed, the reactionsolution was stirred at room temperature for 0.5 horn, followed byaddition of saturated brine (100 mL) and extraction with tetrahydrofuran(50 mL×3). The combined organic phases were dried with anhydrous sodiumsulfate for 30 min, then filtered and concentrated to obtain a crudeproduct. The crude product was subjected to separation by columnchromatography (petroleum ether:ethyl acetate=8:1) to obtain CompoundC283-4 (1.3 g, a colorless oily liquid, yield: 30%).

¹H NMR (400 MHz, CDCl₃): δ 7.41-7.36 (m, 2H), 7.31-7.19 (m, 3H),4.11-4.05 (m, 1H), 3.89 (q, J=7.2 Hz 2H), 3.59-3.54 (m, 1H), 3.17 (brs,1H), 3.10 (brs, 1H), 2.45-2.38 (m, 1H), 1.33 (d, J=6.4 Hz, 3H),2.05-1.18 (m, 6H), 1.06 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 229.9 [M+H]⁺.

Step 4:

Compound C283-4 (800 mg, 2.64 mmol) and 10% wet Pd/C (80 mg) weredissolved in absolute ethanol (20 mL), reacted at room temperature inhydrogen atmosphere for 18 horns, and filtered. The filter cake waswashed twice with ethanol (10 mL), and the filtrate was concentratedunder reduced pressure to obtain Compound C283-5 (500 mg, a colorlessoily liquid, yield: 95%).

MS m/z (ESI): 200.1 [M+H]⁺.

Step 5:

Compound C283-5 (200 mg, 1 mmol) and potassium carbonate (276 mg, 2mmol) were dissolved in tetrahydrofuran (5 mL) and water (5 mL), anddi-tert-butyl dicarbonate (327 mg, 1.5 mmol) was added while stirring,and was stirred at room temperature for 16 hours. LC-MS indicated thatthe reaction of the starting materials was complete. Ethyl acetate (50mL) was added and washed with saturated brine (40 mL×3). The organicphase was dried with anhydrous sodium sulfate for 30 min, and filtered.The filtrate was concentrated under reduced pressure to obtain a crudeproduct of Compound C283-6 (300 mg, a colorless oily liquid, yield:100%).

MS m/z (ESI): 322.2 [M+Na]+.

Step 6:

Compound C283-6 (120 mg, 0.4 mmol) was dissolved in DMF (5 mL). Undernitrogen protection, after added NaH (60%, 24 mg, 0.4 mmol) and stirringfor 1 h, benzyl bromide (82 mg, 0.48 mmol) was added and then stirred atroom temperature for 16 hours. It was quenched by adding water (10 mL),adjusted to pH 5 with 1N acetic acid solution, and then extracted withethyl acetate (20 mL×3). The combined organic phases were washed withsaturated brine (50 mL×3), dried with anhydrous sodium sulfate for 30min and filtered. The filtrate was concentrated under reduced pressureto obtain a crude product of Compound C283-7 (60 mg, a light yellow oilyliquid, yield: 38%).

MS m/z (ESI): 411.9 [M+Na]+.

Step 7:

Compound C283-7 (60 mg, 0.17 mmol) was dissolved in methanol (5 mL).After cooling to 0° C., thionyl chloride (1 mL) was added, and heated upto 40° C., and stirred for 16 horns. LC-MS indicated that the reactionof the starting materials was complete. The reaction solution was cooledto room temperature and concentrated under reduced pressure to obtain acrude product. The crude product was subjected to separation bypreparative high-performance liquid chromatography (CH₃CN:H₂O (0.1%TFA)=20%-50%) to obtain Compound C283-8 (40 mg, a colorless oily liquid,yield: 87%).

¹H NMR (400 MHz, CDCl₃): δ 7.38-7.31 (m, 6H), 4.53 (s, 2H), 4.37-4.35(m, 3H), 4.06 (brs, 1H), 3.77-3.73 (m, 1H), 2.58 (brs, 1H), 2.16-2.10(m, 1H), 1.97-1.90 (m, 1H), 1.83-1.67 (m, 2H), 1.36-1.33 (m, 2H).

MS m/z (ESI): 275.9 [M+H]⁺.

Step 8:

2,2-diphenylacetic acid (37 mg, 0.17 mmol) and DMF (1 drop) were addedto dry dichloromethane (10 mL). After cooling to 0° C., oxalyl chloride(27 mg, 0.21 mmol) was added, stirred at room temperature for 1 horn,and then concentrated under reduced pressure. The residue was dissolvedin dichloromethane (2 mL) to obtain a 2,2-diphenylacetyl chloridesolution. C283-8 (40 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol)were dissolved in dichloromethane (5 mL) and cooled to 0° C. Theprevious 2,2-diphenylacetyl chloride solution was then slowly added. Thereaction solution was allowed to react at room temperature for 5 hours.LC-MS indicated that the reaction of the starting materials wascomplete. Dichloromethane (30 mL) was added, washed with saturated brine(20 mL×3), dried over anhydrous sodium sulfate for 30 min and thenfiltered. The filtrate was concentrated under reduced pressure to obtaina crude compound. The crude product was subjected to separation by thinlayer chromatography (petroleum ether:ethyl acetate=2:1) to obtainCompound C283-9 (30 mg, a colorless oily liquid, yield: 44%).

MS m/z (ESI): 470.0 [M+H]⁺.

Step 9:

C283-9 (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL) andwater (1 mL). Sodium hydroxide (13 mg, 0.32 mmol) was added at roomtemperature, stirred at room temperature for 16 hours, and thenconcentrated under reduced pressure. The residue was dissolved in water(10 mL), adjusted to pH 5 with 1N dilute hydrochloric acid, and thenextracted with ethyl acetate (20 mL×3). The combined organic phases werewashed with saturated brine (30 mL×2), dried over anhydrous sodiumsulfate for 30 min, and then filtered. The filtrate was concentratedunder reduced pressure to obtain a crude product. The crude product wassubjected to separation by preparative high-performance liquidchromatography (CH₃CN:H₂O (0.1% TFA)=20%-70%) to obtain Compound C283(12 mg, a white solid, yield: 41%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.51 (brs, 1H), 7.33-7.19 (m, 15H),5.47-5.43 (m, 1H), 4.48-4.37 (m, 2H), 4.10-4.02 (m, 2H), 3.75-3.73 (m,1H), 3.11-3.07 (m, 1H), 1.80-1.74 (m, 1H), 1.63 (m, 1H), 1.51-1.23 (m,4H).

MS m/z (ESI): 455.8 [M+H]⁺.

The compounds in Table 8 were prepared by methods similar to thatdescribed in Example 9.

TABLE 8 Starting material or reagent Compound different fromCharacterization No. Compound Structure Name that in Example 9 data C291

(1S,3S,4S)-5- ((3-chloro- benzyl) oxy)-2-(2,2- diphenylacetyl)-2-azabicyclo [2.2.2]octane-3- carboxylic acid The benzyl bromide in step6 of Example 9 was replaced with 3-chlorobenzyl bromide. ¹H NMR (400MHz, CD₃OD): δ 7.35-7.23 (m, 14H), 5.41 (s, 1H), 4.56-4.45 (m, 2H),4.29-4.23 (m, 1H). 4.15-4.04 (m, 1H), 3.79 (s, 1H). 2.63-2.49 (m, 1H),2.15-1.80 (m, 3H), 1.69-1.41 (m, 4H). MS m/z (ESI): 490.2 [M + H]⁺. C293

(1S,3S,4S)-5- ((4-chloro- benzyl) oxy)-2-(2,2- diphenylacetyl)-2-azabicyclo [2.2.2]octane-3- carboxylic acid The benzyl bromide in step6 of Example 9 was replaced with 4-chlorobenzyl bromide ¹H NMR (400 MHz,CD₃OD): δ 7.45-7.16 (m, 14H), 5.40 (d, J = 7.1 Hz, 1H), 4.56-4.45 (m,2H), 4.31-4.16 (m, 1H), 4.12-4.01 (m, 1H), 3.79 (d, J = 9.4 Hz, 1H),2.51 (s, 1H), 2.06-1.78 (m, 3H), 1.68-1.38 (m, 4H). MS m/z (ESI): 489.8[M + H]⁺. C294

(1S,3S,4S)-5- ((2-chloro- benzyl) oxy)-2-(2,2- diphenylacetyl)-2-azabicyclo [2.2.2]octane-3- carboxylic acid The benzyl bromide in step6 of Example 9 was replaced with 2-chlorobenzyl bromide. ¹H NMR (400MHz, CD₃OD): δ 7.50-7.10 (m, 14H), 5.44 (d, J = 16.8 Hz, 1H), 4.68-4.48(m, 2H), 4.32-4.16 (m, 1H), 4.12 (d, J = 12.4 Hz, 1H), 3.85 (d, J = 9.3Hz, 1H), 2.54 (s, 1H), 2.06-1.78 (m, 3H), 1.62-1.44 (m, 4H). MS m/z(ESI): 489.8 [M + H]⁺. C290

(1S,3S,4S)-2- (2,2-diphenyl- acetyl)-5-(4- nitrophenoxy)-2- azabicyclo[2.2.2]octane-3- carboxylic acid The benzyl bromide in step 6 of Example9 was replaced with 4-fluoronitrobenzene, and DMF was replaced withtetrahydrofuran. ¹H NMR (400 MHz, CD₃OD): δ 8.22 (d, J = 9.6 Hz, 2H).7.50-7.20 (m, 10H), 7.0 (d, J = 6.8 Hz, 2H), 5.46 (s, 1H), 4.72 (d. J =9.6 Hz, 1H), 4.52 (d, J = 2.8 Hz, 1H), 4.24 (s, 1H). 2.70 (s, 1H),2.50-2.40 (m, 1H), 2.30-2.20 (m, 1H), 1.70-1.50 (m, 4H). MS m/z (ESI):486.9 [M + H]⁺. C296

(1S,3S,4S)-5- (benzyloxy)-2- (diphenyl- carbamoyl)- 2-azabicyclo[2.2.2]octane-3- carboxylic acid The process of preparing2,2-diphenylacetyl chloride in step 8 of Example 9 was completelyreplaced with ¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (brs, 1H), 7.36-7.05(m, 15H), 4.55-4.31 (m, 3H), 3.80 (brs, 2H), 3.61-3.59 (m, 1H), 2.13(brs, 1H), 1.75-1.70 (m, 1H), 1.46-1.24 (m, 4H). MS m/z (ESI): 456.9[M + H]⁺.

C297

(1R,3S,4R)-5- (benzyloxy)- 2-(2,2- diphenylacetyl)- 2-azabicyclo[2.2.2]octanc-3- carboxylic acid

¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (brs, 1H), 7.33-7.19 (m, 15H),5.47-5.44 (m, 1H), 4.49-4.35 (m, 2H), 4.24-4.21 (m, 1H), 4.10-4.00 (m,2H), 3.75-3.62 (m, 1H), 1.80-1.60 (m, 2H), 1.43-1.24 (m, 4H). MS m/z(ESI): 455.9 [M + H]⁺. C302

(1S,3S,4S)-5- (benzyloxy)- 2-(5H-dibenzo [b,f]azepine-5- carbonyl)-2-azabicyclo [2.2.2]octane-3- carboxylic acid The process of preparing2,2-diphenylacetyl chloride in step 8 of Example 9 was completelyreplaced with ¹H NMR (400 MHz, CD₃OD): δ 7.71 (d, J = 6.8 Hz, 1H),7.39-7.25 (m, 11H), 6.99 (d, J = 12.4 Hz, 2H), 4.44 (t, J = 12.0 Hz,2H), 4.36-4.30 (m, 1H), 4.13 (s, 1H), 3.76-3.73 (m, 1H), 2.44 (s, 1H),2.73-2.03 (m, 2H), 1.51-1.29 (m, 2H), 1.05 (s, 1H). MS m/z (ESI): 480.8[M + H]⁺.

Example 10: preparation of(1S,3S,4R)-5-(benzylamino)-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C285) and(1S,3S,4R)-5-(benzyl(methyl)amino)-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C295)

Step 1:

2,2-diphenylacetic acid (383 mg, 1.8 mmol) and DMF (1 drop) were addedto dry dichloromethane (10 mL). After cooling to 0° C., oxalyl chloride(286 mg, 2.2 mmol) was added, stirred at room temperature for 1 horn,and then concentrated under reduced pressure. The residue was dissolvedin ethyl acetate (2 mL) to obtain a 2,2-diphenylacetyl chloridesolution. C283-5 (40 mg, 0.14 mmol) and potassium carbonate (414 mg, 3mmol) were dissolved in ethyl acetate (10 mL) and water (10 mL), andcooled to 0° C. The previous 2,2-diphenylacetyl chloride solution wasthen slowly added. The reaction solution was allowed to react at roomtemperature for 16 hours. LC-MS indicated that the reaction of thestarting materials was complete. Ethyl acetate (30 mL) was added, washedwith saturated brine (20 mL×2), dried over anhydrous sodium sulfate for30 min, and then filtered. The filtrate was concentrated under reducedpressure to obtain a crude compound. The crude product was subjected toseparation by column chromatography (petroleum ether:ethyl acetate=2:1)to obtain Compound C295-1 (350 mg, a white solid, yield: 59%).

¹H NMR (400 MHz, CDCl₃): δ 7.32-7.18 (m, 10H), 5.10 (s, 1H), 4.36 (s,1H), 4.27-4.20 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.92 (brs, 1H), 2.24 (s,1H), 1.99-1.91 (m, 1H), 1.85-1.76 (m, 1H), 1.55-1.50 (m, 1H), 1.46-1.39(m, 1H), 1.29-1.24 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).

MS m/z (ESI): 394.0 [M+H]⁺.

Step 2:

Compound C295-1 (320 mg, 0.81 mmol) was dissolved in dry dichloromethane(20 mL) and Dess-Martin periodinane (690 mg, 1.62 mmol) was added. Thereaction solution was allowed to react at room temperature for 16 hours.LC-MS indicated that the reaction of the starting materials wascomplete. It was then filtered. Dichloromethane (30 mL) was added to thefiltrate, washed with a saturated NaHCO₃ solution (50 mL×2) and thensaturated brine (50 mL×1). After that, it was dried over anhydroussodium sulfate for 30 min, filtered, and concentrated under reducedpressure to obtain a crude compound. The crude product was subjected toseparation by column chromatography (petroleum ether:ethyl acetate=50:1to 30:1) to obtain Compound C295-2 (300 mg, a white solid, yield: 93%).

¹H-NMR (400 MHz, CDCl3): δ 7.37-7.17 (m, 10H), 5.16 (s, 1H), 4.63 (s,1H), 4.38 (s, 1H), 4.24 (q, J=6.4 Hz, 2H), 2.82 (s, 1H), 2.22-2.15 (m,2H), 2.10-2.05 (m, 1H), 1.97-1.91 (m, 1H), 1.77-1.63 (m, 2H), 1.28 (t,J=6.4 Hz, 3H).

MS m/z (ESI): 391.8 [M+H]⁺.

Step 3:

Compound C295-2 (30 mg, 0.077 mmol) was dissolved in methanol (10 mL),and benzylamine (10 mg, 0.092 mmol) and acetic acid (0.1 mL) weresequentially added. After stirring at room temperature for 1 hour,sodium cyanoborohydride (10 mg, 0.154 mmol) was added, stirred at roomtemperature for 16 horns and then concentrated to obtain Compound C295-3(30 mg, a light yellow oily liquid, yield 83%).

MS m/z (ESI): 483.0 [M+H]⁺.

Step 4:

C295-3 (100 mg, 0.2 mmol) was dissolved in methanol (10 mL) and water (3mL). Sodium hydroxide (20 mg, 0.5 mmol) was added at room temperatureand stirred at 50° C. for 16 hours while heating, and then concentratedunder reduced pressure. The residue was dissolved in water (10 mL), andadjusted to pH 5 with 1N diluted hydrochloric acid, followed byextraction with ethyl acetate (20 mL×3). The organic phases were washedwith saturated brine (30 mL×2), dried over anhydrous sodium sulfate for30 min, and then filtered. The filtrate was concentrated under reducedpressure to obtain a crude product. The crude product was subjected toseparation by preparative high-performance liquid chromatography(CH₃CN:H₂O (0.1% TFA)=20%-50%) to obtain Compound C285 (70 mg, a whitesolid, yield: 74%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.64 (brs, 1H), 7.52-7.45 (m, 5H),7.35-7.19 (m, 10H), 5.44 (s, 1H), 4.44 (s, 1H), 4.14-4.11 (m, 3H), 2.10(t, J=12.0 Hz, 1H), 1.66-1.58 (m, 2H), 1.53-1.35 (m, 4H).

MS m/z (ESI): 455.0 [M+H]⁺.

Step 5:

Compound C285 (30 mg, 0.07 mmol) and 30% aqueous formaldehyde solution(12 mg, 0.7 mmol) were dissolved in methanol (3 mL). Acetic acid (0.1mL) and 2N hydrochloric acid (0.2 mL) were then sequentially added andstirred at room temperature for 1 hour. Sodium cyanoborohydride (9 mg,0.14 mmol) was added, and then stirred at room temperature for 16 hour.LC-MS indicated that the reaction of the starting materials wascomplete. After concentration under reduced pressure, a crude productwas obtained. The crude product was subjected to separation bypreparative high-performance liquid chromatography (CH₃CN:H₂O (0.1%TFA)=20%-50%) to obtain Compound C295 (10 mg, a white solid, yield:32%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.78 (brs, 1H), 7.52-7.26 (m, 15H), 5.50(s, 1H), 4.58-4.51 (m, 1H), 4.44-4.39 (m, 2H), 4.19 (brs, 1H), 4.08-4.03(m, 1H), 2.70-2.63 (m, 3H), 2.38-2.33 (m, 1H), 1.80-1.41 (m, 6H).

MS m/z (ESI): 468.8 [M+H]⁺.

The compound in Table 9 was prepared by a method similar to thatdescribed in Example 10.

TABLE 9 Starting material or reagent different from No. CompoundStructure Compound Name that in Example 10 Characterization data C287

(3S)-2-(2,2- diphenylacetyl)- 5-(phenoxyamino)- 2-azabicyclo[2.2.2]octane-3- carboxylic acid Benzylamine in step 3 of Example 10 wasreplaced with phenethylamine ¹H NMR (400 MHz, DMSO-d₆): δ 7.35-7.21 (m,15H), 5.45 (d, J = 6.0 Hz, 1H), 4.44 (s. 1H). 4.26 (s, 1H), 4.13 (s,1H), 4.10 (s, 1H), 3.51 (brs, 1H), 3.13 (s, 1H), 2.94- 2.88 (m, 2H),2.14-2.06 (m, 1H), 1.91-1.34 (m, 5H). MS m/z (ESI): 468.8 [M + H]⁺.

Example 11: preparation of(1S,3S,4S)-2-(2,2-diphenylacetyl)-5-hydroxyl-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C288)

C295-1 (30 mg, 0.08 mmol) was dissolved in tetrahydrofuran (3 mL) andwater (2 mL). Lithium hydroxide (10 mg, 0.38 mmol) was added at roomtemperature, stirred at room temperature for 16 hours, and thenconcentrated under reduced pressure. The residue was dissolved in water(10 mL), adjusted to pH 5 with 1N diluted hydrochloric acid, and thenextracted with ethyl acetate (10 mL×3). The organic phases were washedwith saturated brine (20 mL×2), and then dried over anhydrous sodiumsulfate for 30 min and filtered. The filtrate was concentrated underreduced pressure to obtain a crude product. The crude product wassubjected to separation by preparative high-performance liquidchromatography (CH₃CN:H₂O (0.1% TFA)=20%-60%) to obtain Compound C288(16 mg, a white solid, yield: 57%).

¹H NMR (400 MHz, DMSO-d₆): δ 12.38 (brs, 1H), 7.28-7.20 (m, 10H), 5.41(s, 1H), 4.09 (s, 1H), 3.96 (s, 1H), 3.81-4.77 (m, 1H), 2.10 (s, 1H),1.87-1.79 (m, 1H), 1.87-1.79 (m, 1H), 1.73-1.58 (m, 2H), 1.47-1.41 (m,1H), 1.27-1.21 (m, 1H), 1.13-1.08 (m, 1H).

MS m/z (ESI): 365.9 [M+H]⁺.

Example 12: preparation of(1S,3S,4R)-5-benzamido-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C286)

Step 1:

C295-3 (60 mg, 0.12 mmol) and Pd(OH)₂ (20%, 12 mg) were added to ethanol(10 mL), hydrogenated in a hydrogen atmosphere for 16 horns, and thenfiltered. The filtrate was concentrated under reduced pressure to obtaina crude Compound C286-1 (40 mg, a white solid, yield: 83%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.97 (brs, 2H), 7.34-7.20 (m, 10H), 5.47(s, 1H), 4.40 (s, 1H), 4.17-4.08 (m, 3H), 2.94 (s, 1H), 1.92-1.86 (m,1H), 1.73 (m, 1H), 1.62-1.45 (m, 2H), 1.35-1.28 (m, 2H), 1.20 (t, J=7.2Hz, 3H).

MS m/z (ESI): 393.2 [M+H]⁺.

Step 2:

Compound C286-1 (25 mg, 0.064 mmol) and triethylamine (19 mg, 0.192mmol) were dissolved in dry dichloromethane (5 mL) and then benzoylchloride (10 mg, 0.07 mmol) was added. The reaction solution was reactedat room temperature for 16 hours. LC-MS indicated that the reaction ofthe starting materials was complete. After that, dichloromethane (20 mL)was added, washed with saturated brine (20 mL×2), and then dried overanhydrous sodium sulfate for 30 min. It was then filtered, andconcentrated to obtain a crude product. The crude product was subjectedto separation by preparative thin layer chromatography (petroleumether:ethyl acetate=2:1) to obtain Compound C286-2 (25 mg, a colorlesssolid, yield: 80%).

MS m/z (ESI): 496.7 [M+H]⁺.

Step 3:

C286-2 (25 mg, 0.05 mmol) was dissolved in methanol (10 mL) and water (3mL). Sodium hydroxide (20 mg, 0.5 mmol) was added at room temperatureand stirred at 50° C. for 16 hours while heating, and then concentratedunder reduced pressure. The residue was dissolved in water (10 mL),adjusted to pH 5 with 1N diluted hydrochloric acid, and then extractedwith ethyl acetate (10 mL×3). The organic phases were washed withsaturated brine (30 mL×2), dried over anhydrous sodium sulfate for 30min and then filtered. The filtrate was concentrated under reducedpressure to obtain a crude product. The crude product was subjected toseparation by preparative high-performance liquid chromatography(CH₃CN:H₂O (0.1% TFA)=30%-60%) to obtain Compound C286 (6 mg, a whitesolid, yield: 25%).

¹H NMR (400 MHz, CD₃OD): δ 8.39 (d, J=6.0 Hz, 1H), 7.83-7.79 (m, 2H),7.57-7.53 (m, 1H), 7.49-7.45 (m, 2H), 7.37-7.25 (m, 10H), 5.45 (s, 1H),4.53 (s, 1H), 4.20-4.15 (m, 2H), 2.50 (s, 1H), 1.99-1.50 (m, 6H).

MS m/z (ESI): 468.8 [M+H]⁺.

Example 13: preparation of(1S,3S,4R)-5-((4,4-dimethylpenta-2-alkyne-1-yl)(methyl)amino)-2-(2,2-diphenyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C298)

Step 1:

Compound C298-1 (2.5 g, 30.4 mmol) was dissolved in tetrahydrofuran (50mL), and purged with nitrogen for 3 times. After that, the reactionsolution was cooled to −78° C. under nitrogen protection, n-butyllithiumwas added dropwise (18 ml, 30.4 mmol) and reacted for 2 hours at atemperature not higher than −30° C. After cooling to −78° C. again,paraformaldehyde (1.1 g, 36.7 mmol) was added. After 16 hours ofreaction, the reaction was quenched with saturated aqueous ammoniumchloride solution (50 ml) and extracted with ethyl acetate (100 mL/3).The combined organic phases were dried with anhydrous sodium sulfate(100 g) for 30 min, then filtered and concentrated under reducedpressure to obtain Compound C298-2 (2.4 g, a yellow oily liquid, yield:70.59%).

¹H NMR (400 MHz, DMSO-d₆): δ 5.02 (t, J=6.0 Hz, 1H), 4.01 (d, J=4.0 Hz,2H), 1.18 (s, 9H).

Step 2:

Compound C298-2 (2.0 g, 17.8 mmol) was dissolved in tetrahydrofuran (50mL). Tosyl chloride (6.8 g, 35.6 mmol) and potassium hydroxide (3.0 g,53.4 mmol) were added and allowed to react at room temperature for 16hours, and then filtered. The filtrate was concentrated under reducedpressure to obtain a crude product. The crude product was dissolved inethyl acetate (100 ml), and washed with saturated brine (100 ml×2). Thecombined organic phases were dried with anhydrous sodium sulfate (50 g)for 30 min, and then filtered. The filtrate was concentrated underreduced pressure to obtain Compound C298-3 (1 g, an orange oily liquid,yield: 43.5%).

MS m/z (ESI): 267.1 [M+H]⁺.

Step 3:

Compound C298-4 (400 mg, 0.83 mmol) was dissolved in dry dichloromethane(40 mL). An aqueous formaldehyde solution (2 ml) and acetic acid (1 mL)were added, and stirred at room temperature for 4 hours. After that,sodium triacetoxyborohydride (703.6 mg, 3.32 mmol) was added, andstirring was continued for 16 hours. LC-MS indicated that the reactionof the starting materials was complete. It was then washed withsaturated brine (20 ml×3), dried over anhydrous sodium sulfate (10 g)for 30 min, filtered and then concentrated to obtain a crude product.The crude product was subjected to separation by column chromatography(petroleum ether:ethyl acetate=1:1) to obtain Compound C298-5 (200 mg, alight yellow oily liquid, yield: 48.66%).

MS m/z (ESI): 497.1[M+H]⁺.

Step 4:

Compound C298-5 (200 mg, 0.4 mmol) was dissolved in isopropyl alcohol(50 mL), and palladium hydroxide/carbon (50 mg) was added. It was purgedwith hydrogen for 3 times, and stirred at room temperature for 4 hours.LC-MS indicated that the reaction of starting materials was complete. Itwas then filtered, and the filtrate was concentrated to obtain CompoundC298-6 (60 mg, a light yellow oily liquid, yield 36.8%).

MS m/z (ESI): 407.2 [M+H]⁺.

Step 5:

Compound C298-6 (60 mg, 0.15 mmol) was dissolved in tetrahydrofuran (20mL), and anhydrous potassium carbonate (61.2 mg, 0.44 mmol) and C298-3(80 mg, 0.3 mmol) were added. After stirring for 8 hours at roomtemperature, LC-MS indicated that a product was produced. It wasfiltered, and the filtrate was concentrated. The residue was subjectedto separation by preparative high performance liquid chromatography, andlyophilized to obtain Compound C298-7 (8 mg, a white solid, yield:11.0%).

MS m/z (ESI): 501.1 [M+H]⁺.

Step 6:

Compound C298-7 (8 mg, 0.016 mmol) was dissolved in methanol (10 mL),and water (3 mL), sodium hydroxide (5.12 mg, 0.13 mmol) were added andstirred at 50° C. for 16 hours. The reaction solution was concentrated,subjected to separation by preparative high performance liquidchromatography (water:acetonitrile=60:40), and lyophilized to obtainCompound C298 (4.4 mg, a white solid, yield: 58.3%).

¹H NMR (400 MHz, CD₃OD): δ 7.29 (m, 10H), 5.40 (s, 1H), 4.41 (s, 1H),4.10 (s, 1H), 3.80 (d, J=16.8 Hz, 1H), 3.59 (d, J=17.1 Hz, 1H), 2.90 (s,1H), 2.50 (s, 3H), 2.07-2.01 (m, 2H), 1.86-1.83 (m, 2H), 1.43 (m, 2H),1.30-1.18 (m, 9H).

MS m/z (ESI): 473.1 [M+H]⁺.

Example 14: preparation of(1S,3S,4R)-2-(2,2-diphenylacetyl)-5-((3-(4-fluorophenyl)prop-2-yn-1-yl)(methyl)amino)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (C299)

Step 1:

Compound C299-1 (1.0 g, 4.5 mmol) was dissolved in tetrahydrofuran (50mL), and Copper iodide (85.7 mg, 0.45 mmol),bis(triphenylphosphine)palladium dichloride (315.9 mg, 0.45 mmol) andpropynol (378.4 mg, 6.75 mmol) were added, purged with nitrogen for 3times, and stirred at room temperature for 16 horns under nitrogenprotection. Water (50 mL) was added and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried with anhydrous sodium sulfate (30 g) for 30 min and thenfiltered. The filtrate was concentrated under reduced pressure, andsubjected to separation by column chromatography (petroleum ether:ethylacetate=70:30) to obtain Compound C299-2 (642 mg, a yellow oily liquid,yield: 95.0%).

¹H NMR (400 MHz, CDCl₃): δ 7.43 (dd, J=5.6, 8.4 Hz, 2H), 7.05-6.95 (m,2H), 4.51 (s, 2H).

Step 2:

Compound C299-2 (642 mg, 4.27 mmol) was dissolved in tetrahydrofuran (50mL), and tosyl chloride (1.63 g, 8.55 mmol) and potassium hydroxide(956.5 mg, 17.8 mmol) were added. The reaction was carried out at roomtemperature for 16 hours, and then filtered. The filtrate wasconcentrated under reduced pressure to obtain a crude product. The crudeproduct was dissolved in ethyl acetate (100 ml). The organic phase waswashed with saturated brine (100 ml×2), dried with anhydrous sodiumsulfate (50 g) for 30 min and then filtered. The filtrate wasconcentrated under reduced pressure to obtain Compound C299-3 (360 mg,an orange oily liquid, yield: 27.7%).

MS m/z (ESI): 305.3 [M+H]⁺.

Step 3:

Compound C298-6 (100 mg, 0.25 mmol) prepared according to Step 3 andStep 4 of Example 10 was dissolved in tetrahydrofuran (20 mL), andanhydrous potassium carbonate (101.8 mg, 0.74 mmol) and C299-3 (115 mg,0.37 mmol) were added and stirred for 8 hours at room temperature. LC-MSindicated that a product is produced. After filtration, the filtrate wasconcentrated and subjected to separation by column chromatography(petroleum ether:ethyl acetate=60:40) to obtain Compound C299-4 (28 mg,a transparency liquid, yield: 21.2%).

MS m/z (ESI): 538.9 [M+H]⁺.

Step 4:

Compound C299-4 (28 mg, 0.052 mmol) was dissolved in methanol (10 mL),and water (3 mL) and sodium hydroxide (5.12 mg, 0.13 mmol) were addedand stirred at 50° C. for 16 hours. The reaction solution wasconcentrated and subjected to separation by preparative high performanceliquid chromatography (water:acetonitrile=60:40), and then lyophilizedto obtain Compound C299 (6.5 mg, a white solid, yield: 25.0%).

¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.63-7.54 (m, 2H), 7.36-7.14(m, 12H), 5.46 (s, 1H), 4.50 (s, 1H), 4.30-4.24 (m, 1H), 3.51 (s, 1H),3.01 (s, 2H), 2.95 (s, 2H), 2.88 (s, 2H), 2.23-2.21 (m, 1H), 1.96-1.87(m, 2H), 1.77-1.71 (m, 2H), 1.60-1.46 (m, 2H).

MS m/z (ESI): 510.9 [M+H]⁺.

Example 15: preparation of(1R,2S,5S)-2-((N,N-dimethylsulphamoyl)carbamoyl)-3-(2,2-diphenylacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid (C233)

Compound C34 (130 mg, 0.26 mmol) was dissolved in a dichloromethanesolution (20 mL). N,N-dimethylsulfamoylamide (49 mg, 0.4 mmol), DCC (82mg, 0.4 mmol) and DMAP (15 mg, 0.13 mmol) were added to the solutionsequentially, and reacted at room temperature for 16 hours. After thereaction was complete, 20 mL water was added to the reaction solutionand extracted with dichloromethane (20 mL×2). The organic phases werecombined, dried with anhydrous sodium sulfate (10 g) for 30 min,filtered, and concentrated under reduced pressure to obtain a crudeproduct. The crude product was purified by preparative high-performanceliquid chromatography (acetonitrile/water (0.1% trifluoroacetic acidsolution), 50/50 to 90/10) to obtain Compound C233 (50 mg, a lightyellow solid, yield: 32%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (brs, 1H), 7.49-7.11 (m, 15H), 5.52(s, 1H), 5.20-5.05 (m, 1H), 5.02-4.80 (m, 1H), 4.66 (s, 2H), 4.23 (s,1H), 3.80-3.65 (m, 1H), 3.47-3.42 (m, 1H), 2.75 (s, 6H), 1.95-1.80 (m,1H), 1.72-1.60 (m, 1H), 1.55-1.40 (m, 1H), 1.25-1.05 (m, 1H).

MS m/z (ESI): 591.0 [M+H]⁺.

Example 16: preparation of(1R,2S,5S)-8-((4-allylbenzyl)(methyl)carbamoyl)-3-(diphenylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C235) and(1R,2S,5S)-3-(diphenylcarbamoyl)-8-(methyl(4-propylbenzyl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylicacid (C236)

Step 1:

Compound C165-1 (121 mg, 0.13 mmol) was dissolved in dry toluene (20mL). SM1 (100 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium(26 mg, 0.02 mmol) were sequentially added and allowed to react at 100°C. for 16 horns under nitrogen protection. LC-MS indicated that thereaction of the starting materials was complete. The reaction solutionwas concentrated under reduced pressure to evaporate off toluene, thendissolved in ethyl acetate (30 mL) and washed once with saturated brine(30 mL). After that, the organic phase was dried over anhydrous sodiumsulfate (20 g) for half an horn, filtered, and concentrated. Theresulting crude product was subjected to separation by preparative platechromatography (ethyl acetate:petroleum ether=1:2) to obtain CompoundC235-1 (70 mg, a white solid, yield: 61%).

MS m/z (ESI): 566.8 [M+H]⁺.

Step 2:

Compound C235-1 (70 mg, 0.13 mmol) was dissolved in dry methanol (30 mL)and water (10 mL), and sodium hydroxide (21 mg, 0.52 mmol) was added.The reaction solution was allowed to react at 40° C. for 16 horns. LC-MSindicated that the reaction of starting materials was complete. Thereaction solution was concentrated under reduced pressure to remove thesolvent, dissolved in water (30 mL) and adjusted to pH=4 to 5 with 2NHCl solution, leading to a white precipitate. The reaction solution wasfiltered, and the white solid was rinsed with water (10 mL). After that,it was concentrated under reduced pressure, and the white solid wasdried by rotary vaporization to remove water therein, obtaining compoundC235 (60 mg, a white solid, yield: 90%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.98 (s, 1H), 7.38-7.32 (m, 4H), 7.19-7.11(m, 6H), 7.04-6.96 (m, 4H), 5.95 (s, 1H), 5.12-4.98 (m, 2H), 4.43-4.19(m, 4H), 3.91 (s, 1H), 3.46-3.34 (m, 4H), 2.68 (s, 3H), 1.78-1.22 (m,4H).

MS m/z (ESI): 538.8 [M+H]⁺.

Step 3:

Compound C235 (53 mg, 0.1 mmol) was dissolved in ethyl acetate (20 mL).Pd/C catalyst (10 mg) was added, and the reaction was carried out atroom temperature under the protection of H₂ for 0.5 hour. LC-MSindicated that the reaction of the starting materials was complete. Thereaction solution was filtered, concentrated to obtain Compound C236 (30mg, a white solid, yield: 57%).

¹H NMR (400 MHz, DMSO-cfc) δ 13.02 (s, 1H), 7.37-7.31 (m, 4H), 7.18-7.12(m, 6H), 7.04-6.96 (m, 4H), 4.40-4.20 (m, 3H), 3.91 (s, 1H), 3.46-3.34(m, 3H), 2.68 (s, 3H), 2.56-2.52 (m, 2H), 1.78-1.22 (m, 6H), 0.88 (t,J=7.2 Hz, 3H).

MS m/z (ESI): 540.8 [M+H]⁺.

The compounds in Table 10 were prepared by methods similar to thatdescribed in Example 16.

TABLE 10 Starting material or reagent different from No. CompoundStructure Compound Name that in Example 16 Characterization data C170

(1R,2S,5S)-3- (diphenylcarbamoyl)-8- (methyl(4-vinylbenzyl) carbamoyl)-3,8-diazabicyclo[3.2.1] octane-2-carboxylic acid SMI in step 1 wasreplaced with tributyl(vinyl) stannane. The reaction in step 3 did nottake place. ¹H NMR (400 MHz, DMSO-d₆) δ 12.98 (s, 1H), 7.45-7.32 (m,6H), 7.22-7.14 (m, 4H), 7.06- 6.98 (m, 4H), 6.72 (dd, J = 17.6, 11.0 Hz,1H), 5.81 (d. J = 17.6 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.46-4.20 (m4H), 3.92 (s, 1H), 3.39 (dd, J = 26.1, 11.8 Hz, 2H), 2.70 (s, 3H),1.77-1.27 (m, 4H). MS m/z (ESI): 524.8 [M + H]⁺. C164

(1R,2S,5S)-3- (diphenylcarbamoyl)-8- ((4-ethylbenzyl)(methyl)carbamoyl)-3,8- diazabicyclo[3.2.1] octane-2-carboxylic acid SMIin step 1 was replaced with tributyl(vinyl) stannane. ¹H NMR (400 MHz,DMSO-d₆) δ 13.00 (s, 1H), 7.38-7.34 (m, 4H), 7.18-7.08 (m, 6H), 7.04-6.96 (m, 4H), 4.44-4.18 (m, 4H), 3.91 (s, 1H), 3.49-3.36 (m, 2H), 2.68(s, 3H), 2.58 (dd, J = 15.0, 7.5 Hz, 2H), 1.74-1.24 (m, 4H), 1.17 (t, J= 7.5 Hz, 3H). MS m/z (ESI): 526.8 [M + H]⁺.

Biological Assay

Measurement of Inhibitory Activity on AT₁ Receptor (AT₄R)/AT₂ Receptor(AT₂R)

Through the following steps, the inhibitory activity of the compound onAT₁R/AT₂R (IC₅₀ value) was determined:

1) An appropriate amount of 1×TLB (Tag-lite Buffer) was prepared andwell mixed for use.

2) The compound was diluted by 10 times with ddH₂O or DMSO. The compoundwas then dilute to 4 times of the working concentration with 1×TLB andmixed well for use.

3) 8600 nM Tag-lite angiotensin receptor red agonist was diluted to 12nM (4×Kd) with 1×TLB.

4) 5 ml 1×TLB was taken into a 15 ml centrifuge tube.

5) After thawing 1 lube of Tb-labeled AT₁R/AT₂R cells in a 37° C. waterbath, the cells were quickly transferred to the 1×TLB in step 4), mixedgently, and centrifuged at 1200 g for 5 minutes at room temperature.

6) The supernatant was aspirated gently, and the cells were resuspendedand mixed in 2.7 ml 1×TLB, and then placed at room temperature untiluse.

7) 10 μl cells were added to all test wells, and 5 μl 4× workingsolution of the compound from step 2) was added to the correspondingtest wells. 5 μl 4× Tag-lite angiotensin receptor red agonist welldiluted in step 3) was added to all test wells.

8) After leaving the reaction plate at room temperature for 1 h, datawere measured and analyzed using Envision HTRF Reader, and the halfinhibitory concentration (IC₅₀) of the compound on AT₁R/AT₂R wascalculated with the GraphPad Prism four-parameter equation.

The measured IC₅₀ values of the compounds are shown in Table 11 below.

TABLE 11 No. AT₂R IC₅₀ (nM) AT₁R IC₅₀ (nM) C1  6.67 >10000 C2  9.11 NAC3  13.86 NA C4  9.82 NA C5  15.26 >10000 C7  82.71 NA C9  107.4 NA C10 58.77 >10000 C12  17.11 >10000 C13  22.25 NA C14  29.39 >10000 C28 473.30 NA C34  35.19 >10000 C35  36.60 NA C36  20.66 NA C37 55.33 >10000 C41  9.765 NA C45  84.69 NA C62  104.00 NA C68 58.12 >10000 C69  169.80 NA C71  50.44 >10000 C72  19.07 NA C75  54.03NA C76  69.65 NA C78  55.01 >10000 C79  24.63 >10000 C82  3.98 >10000C83  18.10 >10000 C112 21.51 >10000 C113 12.1 NA C114 26.39 NA C115431.1 NA C117 61.26 NA C120 349.90 NA C123 11.73 >10000 C124 37.83 NAC125 19.00 NA C126 78.03 NA C128 21.46 NA C129 147.80 NA C131 495.10 NAC132 481.50 NA C133 243.2 NA C134 322.10 NA C138 11.66 NA C140 5.49 NAC141 7.99 NA C142 653.5 NA C143 9.97 NA C144 21.57 NA C145 110.00 NAC146 14.04 NA C147 111.10 NA C148 7.26 NA C149 16.58 >10000 C1509.82 >10000 C151 74.32 NA C152 47.37 NA C153 2.78 NA C154 19.83 NA C1559.03 >10000 C156 10.14 NA C157 27.06 >10000 C161 30.49 NA C1624.04 >10000 C163 65.60 NA C164 4.35 NA C165 14.00 NA C166 4.42 >10000C167 18.9 >10000 C169 7.26 NA C170 3.87 NA C171 19.16 NA C173 5.57 NAC174 225.7 NA C182 431.9 NA C184 41.67 NA C185 38.75 NA C186 64.56 NAC187 3.75 NA C188 7.11 NA C189 4.04 NA C194 129.20 NA C196 1.63 NA C1975.52 NA C198 10.19 NA C200 3.25 NA C201 18.43 NA C202 3.866 NA C20313.68 NA C204 4.931 NA C205 42.84 NA C206 10.08 NA C207 10.36 NA C20811.84 NA C209 81.39 NA C210 49.55 NA C212 9.038 NA C213 5.92 NA C21411.33 NA C215 26.47 NA C216 3.22 NA C217 9.13 NA C218 11.48 NA C21919.79 NA C220 12.49 NA C221 76.67 NA C222 11.67 NA C223 7.87 NA C22423.84 NA C225 11.68 NA C226 12.67 NA C227 18.27 NA C229 10.07 NA C23050.24 NA C231 103.2 NA C233 102.50 NA C235 6.78 NA C236 6.13 NA C23737.60 NA C239 160.8 NA C240 113.30 NA C241 155.50 NA C245 10.52 NA C24610.05 NA C249 10.88 NA C252 16.18 NA C255 13.77 NA C256 39.97 NA C259244.80 NA C260 29.59 NA C265 27.25 NA C266 1.63 NA C269 68.22 NA C27114.53 NA C272 16.60 NA C273 20.93 NA C274 19.77 NA C277 10.46 NA C27810.56 NA C279 24.19 NA C281 20.29 NA C283 46.30 >10000 C286 760.20 NAC290 560.90 NA C291 765.20 NA C294 665.90 NA Note: NA means Not Assayed.

Various modifications of the invention in addition to those describedherein will become apparent to those skilled in the art from theforegoing description. Such modifications are intended to fall withinthe scope of the appended claims. Each reference, including all patents,applications, journal articles, books and any other disclosure, referredto herein is hereby incorporated by reference in its entirety.

1. A compound or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein the compound has astructure of formula (I) or formula (F):

wherein: the ring C atom at the position marked with the symbol “*” isconnected to the ring C atom at the position marked with the symbol “#”or “##” through a U group; U is selected from the group consisting of asingle bond; NR¹⁰; C₁₋₃ alkylene, in which 1 or 2 CH₂ moieties areoptionally replaced with a group independently selected from the groupconsisting of O, S, and NR¹⁰; and C₂₋₃ alkenylene, in which any one ofthe CH moieties forming a C═C double bond is optionally replaced with N;X³ is CR¹⁰ or N; R is:

wherein 1) R^(1a), R^(1b) together with X¹ to which they are attachedform a saturated or partially unsaturated C₃₋₁₀ cyclic hydrocarbylgroup, a saturated or partially unsaturated 3- to 10-memberedheterocyclic group, a C₆₋₁₀ aryl or a 5- to 14-membered heteroaryl; andX⁴ is a direct bond; or 2) R^(1a) is selected from the group consistingof C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is optionallyreplaced with O or S; a saturated or partially unsaturated C₃₋₁₀ cyclichydrocarbyl group; a saturated or partially unsaturated 3- to10-membered heterocyclic group; C₆₋₁₀ aryl; 5- to 14-memberedheteroaryl; —C₁₋₆ alkylene-saturated or partially unsaturated C₃₋₁₀cyclic hydrocarbyl group; —C₁₋₆ alkylene-saturated or partiallyunsaturated 3- to 10-membered heterocyclic group; —C₁₋₆ alkylene-C₆₋₁₀aryl; and —C₁₋₆ alkylene-(5- to 14-membered heteroaryl); R^(1b) does notexist, or is selected from the group consisting of H and R^(1a); X¹ doesnot exist, or is CR¹⁰ or N; or R^(1b) and X¹ together form a saturatedor partially unsaturated bivalent C₃₋₁₀ cyclic hydrocarbyl group or asaturated or partially unsaturated bivalent 3- to 10-memberedheterocyclic group; X⁴ is selected from the group consisting of a directbond; C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,—O—S(═O)_(r), —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(r), wherein O, S, NR¹⁰ areconnected to X¹; preferably is a direct bond, C(═O), S(═O)_(y),—OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(y)—; providedthat: when X⁴ is a direct bond, X¹ is CR¹⁰ or N; or 3) R^(1a) and R^(1b)are each independently C₃₋₁₀ cyclic hydrocarbyl group; 3- to 10-memberedheterocyclic group, C₆₋₁₀ aryl, or 5- to 14-membered heteroaryl, and anavailable ring atom on R^(1a) is connected to an available ring atom onR^(1b) through Y group, such that R^(1a) and R^(1b) together with X¹ towhich they are attached form an optionally substituted saturated orpartially unsaturated fused ring system containing 3 or more rings; X¹is CR¹⁰ or N; X⁴ is selected from the group consisting of C(═O);S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—, —O—S(═O)_(y)—,—NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ are connected toX¹; preferably is C(═O) or S(═O)_(y); and Y is selected from the groupconsisting of a single bond; NR¹⁰; C₁₋₃ alkylene, in which 1 or 2 CH₂moieties are optionally replaced with a group independently selectedfrom the group consisting of O, S, and NR¹⁰; and C₂₋₃ alkenylene, inwhich any one of the CH moieties forming a C═C double bond is optionallyreplaced with N; or

wherein X⁶ is selected from the group consisting of O; S; NR¹⁰; and—C(═O)—NR¹⁰— and —S(═O)_(y)—NR¹⁰—, wherein C(═O) and S(═O)_(y) areconnected to R⁹; R⁹ is selected from the group consisting of H, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland C₆₋₁₂ aralkyl; R′ is:

wherein (1) R^(2a), R^(2b) together with X² to which they are attachedform a saturated or partially unsaturated C₃₋₁₀ cyclic hydrocarbylgroup, a saturated or partially unsaturated 3- to 10-memberedheterocyclic group, a C₆₋₁₀ aryl or a 5- to 14-membered heteroaryl; andX⁵ is a direct bond; or (2) R^(2a) is selected from the group consistingof C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, wherein any one of the CH₂moieties in the C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl is optionallyreplaced with O or S; a saturated or partially unsaturated C₃₋₁₀ cyclichydrocarbyl group; a saturated or partially unsaturated 3- to10-membered heterocyclic group; C₆₋₁₀ aryl; 5- to 14-memberedheteroaryl; —C₁₋₆ alkylene-saturated or partially unsaturated C₃₋₁₀cyclic hydrocarbyl group; —C₁₋₆ alkylene-saturated or partiallyunsaturated 3- to 10-membered heterocyclic group; —C₁₋₆ alkylene-C₆₋₁₀aryl; and —C₁₋₆ alkylene-(5- to 14-membered heteroaryl); R^(2b) does notexist, or is selected from the group consisting of H and R^(2a); X² doesnot exist, or is CR¹⁰ or N; or R^(2b) and X² together form a saturatedor partially unsaturated bivalent C₃₋₁₀ cyclic hydrocarbyl group or asaturated or partially unsaturated bivalent 3- to 10-memberedheterocyclic group; X⁵ is selected from the group consisting of a directbond; C(═O); S(═O)_(y); O; S; NR¹⁰; and —OC(═O)—, —SC(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein O, S, NR¹⁰ areconnected to X²; preferably is a direct bond, C(═O), S(═O)_(y),—OC(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(y)—; providedthat: when X⁵ is a direct bond, X² is CR¹⁰ or N; or (3) R^(2a) andR^(2b) are each independently C₃₋₁₀ cyclic hydrocarbyl group; 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, or 5- to 14-memberedheteroaryl, and an available ring atom on R^(2a) is connected to anavailable ring atom on R^(2b) through Z group, such that R^(2a) andR^(2b) together with X² to which they are attached form an optionallysubstituted saturated or partially unsaturated fused ring systemcontaining 3 or more rings; X² is CR¹⁰ or N; X⁵ is selected from thegroup consisting of C(═O); S(═O)_(y); O; S; NR¹⁰; and —O—C(═O)—,—S—C(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein O,S, NR¹⁰ are connected to X²; preferably is C(═O) or S(═O)_(y); and Z isselected from the group consisting of a single bond; NR¹⁰; C₁₋₃alkylene, in which 1 or 2 CH₂ moieties are optionally replaced with agroup independently selected from the group consisting of O, S, andNR¹⁰; and C₂₋₃ alkenylene, in which any one of the CH moieties forming aC═C double bond is optionally replaced with N; R³, R⁴ and R¹⁰ are eachindependently selected from the group consisting of H, halogen, cyano,nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cyclic hydrocarbylgroup, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹, —P(O)(OR¹¹)(OR¹²),—OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₇,alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene —C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹² and —O—C₁₋₆ alkylene-NR¹¹R¹²; R¹¹ and R¹², at eachoccurrence, are each independently selected from the group consisting ofH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-O—, C₁₋₆ alkyl-S—,C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-membered heterocyclic group,C₆₋₁₀ aryl, 5- to 14-membered heteroaryl and C₆₋₁₂ aralkyl; h and k areeach independently 1, 2, 3, 4, 5 or 6; the above alkyl, alkylene,alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclicgroup, aryl, heteroaryl and aralkyl, at each occurrence, are eachoptionally substituted by 1, 2, 3 or more R¹³, wherein the R¹³, at eachoccurrence, is independently selected from the group consisting ofhalogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cyclic hydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀aryl, 5- to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹,—P(O)R¹¹R¹², —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₆alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹², and wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryland aralkyl recited for the substituent R¹³ are optionally furthersubstituted by 1, 2, 3 or more substituents independently selected fromthe group consisting of halogen, OH, oxo, amino, cyano, nitro, C₁₋₆alkyl, halogenated C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₃₋₆ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, 5-to 14-membered heteroaryl and C₆₋₁₂ aralkyl; and wherein theheterocyclic group, aryl or heteroaryl when being a substituent isconnected to the rest of the molecule through a ring C atom, or wherepossible, through a ring N atom; x, at each occurrence, is independently0, 1 or 2; y and z, at each occurrence, are each independently 1 or 2.2. The compound according to claim 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of formula (I):

wherein: R³, R⁴ and R¹⁰ are each independently selected from the groupconsisting of H, halogen, cyano, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to 10-membered heterocyclicgroup, C₆₋₁₀ aryl, 5- to 14-membered heteroaryl, C₆₋₁₂ aralkyl, —OR¹¹,—SR¹¹, —OC(═O)R¹¹, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹,—S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹²,—NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹², —NR¹¹—S(═O)_(y)—R¹²,—NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₆ alkylene-R¹¹, —C₁₋₆ alkylene-OR¹¹, —C₁₋₆alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹²; and R¹³, at eachoccurrence, is independently selected from the group consisting ofhalogen, cyano, nitro, C₁₋₆ alkyl, C₃₋₁₀ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-memberedheteroaryl, C₆₋₁₂ aralkyl, —OR¹¹, —SR¹¹, —OC(═O)R¹¹, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)R¹¹, —S(═O)_(y)OR¹¹,—S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹S(═O)_(z)OR¹², —S(═O)_(y)NR¹¹C(═O)R¹²,—S(═O)_(y)NR¹¹C(═O)OR¹², —NR¹¹R¹², —NR¹¹—C(═O)R¹², —NR¹¹—C(═O)OR¹²,—NR¹¹—S(═O)_(y)—R¹², —NR¹¹—C(═O)—NR¹¹R¹², —C₁₋₇, alkylene-R¹¹, —C₁₋₆alkylene-OR¹¹, —C₁₋₆ alkylene-OC(═O)R¹¹, —C₁₋₆ alkylene-C(═O)OR¹¹, —C₁₋₆alkylene-S(═O)_(x)R¹¹, —C₁₋₆ alkylene-S(═O)_(y)OR¹¹, —C₁₋₆alkylene-OC(═O)NR¹¹R¹², —C₁₋₆ alkylene-C(═O)NR¹¹R¹², —C₁₋₆alkylene-C(═O)NR¹¹—S(═O)_(y)R¹², —C₁₋₆ alkylene-NR¹¹—C(═O)NR¹¹R¹², —C₁₋₆alkylene-OS(═O)_(y)R¹¹, —C₁₋₆ alkylene-OS(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-S(═O)_(y)NR¹¹R¹², —C₁₋₆ alkylene-NR¹¹—S(═O)_(y)NR¹¹R¹², —C₁₋₆alkylene-NR¹¹R¹², and —O—C₁₋₆ alkylene-NR¹¹R¹², and wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryland aralkyl recited for the substituent R¹³ are optionally furthersubstituted by 1, 2, 3 or more substituents independently selected fromthe group consisting of halogen, OH, oxo, amino, cyano, nitro, C₁₋₆alkyl, halogenated C₁₋₆ alkyl, C₃₋₆ cyclic hydrocarbyl group, 3- to10-membered heterocyclic group, C₆₋₁₀ aryl, 5- to 14-membered heteroaryland C₆₋₁₂ aralkyl; and wherein the heterocyclic group, aryl orheteroaryl when being a substituent is connected to the rest of themolecule through a ring C atom, or where possible, through a ring Natom.
 3. The compound according to claim 1, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein Uis a single bond, NR¹⁰, O, S, methylene, ethylene, —CH₂—O—, —O—CH₂—,—CH₂—S—, —S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—, —CH═CH—, —CH═N— or —N═CH—;preferably, U is a single bond, methylene or ethylene.
 4. The compoundaccording to claim 1, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R³ is F, Cl, Br, I,amino, cyano, nitro, C₁₋₄ alkyl, C₅₋₇ cyclic hydrocarbyl group, 5- to7-membered monocyclic heterocyclic group, phenyl, 5- to 7-memberedheteroaryl, —OR¹¹, —SR¹¹, —OC(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹,—S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹²,—C₁₋₄ alkylene-OR¹¹, —C₁₋₄ alkylene-OC(═O)R¹¹, —C₁₋₄ alkylene-C(═O)OR¹¹,—C₁₋₄ alkylene-S(═O)_(y)OR¹¹, —C₁₋₄ alkylene-OC(═O)NR¹¹R¹², —C₁₋₄alkylene-C(═O)NR¹¹R¹², —C₁₋₄ alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄alkylene-S(═O)_(y)NR¹¹R¹²; preferably is 5- to 6-membered heteroaryl,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₃alkylene-OC(═O)R¹¹, —C₁₋₃ alkylene-C(═O)OR¹¹, —C₁₋₃alkylene-S(═O)_(y)OR¹¹, —C₁₋₃ alkylene-C(═O)NR¹¹R¹² or —C₁₋₃alkylene-S(═O)_(y)NR¹¹R¹²; more preferably is 5- to 6-memberedheteroaryl (such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl such as 1-tetrazolyl or 5-tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl), —C(═O)OR¹¹ (such asCOOH, COOCH₃ or COOCH₂CH₃), —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹² (such as

—C(═O)NR¹¹S(═O)_(y)R¹² (such as

—C(═O)NR¹¹R¹², —S(═O)_(y)OR¹¹ or —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹² (such as

or R³ is —P(O)(OR¹¹)(OR¹²), preferably —P(O)(OH)₂, —P(O)(OH)(OC₁₋₆alkyl) or —P(O)(OC₁₋₆ alkyl)₂, preferably —P(O)(OH)₂, —P(O)(OH)(OC₁₋₃alkyl) or —P(O)(OC₁₋₃ alkyl)₂, more preferably —P(O)(OH)₂,—P(O)(OH)(OCH₃) or —P(O)(OH)(OCH₂CH₃).
 5. (canceled)
 6. The compoundaccording to claim 1, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R⁴ and R¹⁰, at eachoccurrence, are each independently H, F, Cl, Br, I, amino, cyano, nitro,C₁₋₄ alkyl, C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclicheterocyclic group, phenyl, 5- to 6-membered heteroaryl, —OR¹¹, —SR¹¹,—OC(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹, —S(═O)_(y)NR¹¹R¹²,—S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹², —C₁₋₄ alkylene-OR¹¹,—C₁₋₄ alkylene-OC(═O)R¹¹, —C₁₋₄ alkylene-C(═O)OR¹¹, —C₁₋₄alkylene-S(═O)_(y)OR¹¹, —C₁₋₄ alkylene-OC(═O)NR¹¹R¹², —C₁₋₄alkylene-C(═O)NR¹¹R¹², —C₁₋₄ alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄alkylene-S(═O)_(y)NR¹¹R¹²; preferably H, F, Cl, Br, I, OH, amino, cyano,nitro or C₁₋₄ alkyl (e.g. methyl).
 7. The compound according to claim 1,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R¹¹ and R¹² at each occurrence are each independentlyselected from the group consisting of H, C₁₋₄ alkyl, C₅₋₇ cyclichydrocarbyl group, 5- to 7-membered monocyclic heterocyclic group,phenyl, 5- to 6-membered heteroaryl; preferably selected from the groupconsisting of H and C₁₋₄ alkyl; the alkyl, cyclic hydrocarbyl group,heterocyclic group, phenyl and heteroaryl are each optionallysubstituted by 1, 2, 3 or more R¹³.
 8. The compound according to claim1, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein R¹³, at each occurrence, is independentlyselected from the group consisting of F, Cl, Br, I, amino, cyano, nitro,C₁₋₄ alkyl, C₅₋₇ cyclic hydrocarbyl group, 5- to 7-membered monocyclicheterocyclic group, phenyl, 5- to 6-membered heteroaryl, C₆₋₁₂ aralkyl,—OR¹¹, —SR¹¹, —OC(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)NR¹¹S(═O)_(y)NR¹¹R¹², —C(═O)NR¹¹S(═O)_(y)R¹², —S(═O)_(y)OR¹¹,—S(═O)_(y)NR¹¹R¹², —S(═O)_(y)NR¹¹C(═O)R¹², —S(═O)_(y)NR¹¹C(═O)OR¹²,—C₁₋₄ alkylene-R¹¹, —C₁₋₄ alkylene-OR¹¹, —C₁₋₄ alkylene-OC(═O)R¹¹, —C₁₋₄alkylene-C(═O)OR¹¹, —C₁₋₄ alkylene-S(═O)_(y)OR¹¹, —C₁₋₄alkylene-OC(═O)NR¹¹R¹², —C₁₋₄ alkylene-C(═O)NR¹¹R¹², —C₁₋₄alkylene-OS(═O)_(y)R¹¹ or —C₁₋₄ alkylene-S(═O)_(y)NR¹¹R¹²; preferably isF, Cl, Br, I, amino, cyano, nitro, CM alkyl, —OR¹¹ (preferably, R¹¹ is aC₁₋₆ alkyl optionally substituted by 1, 2, 3 or more halogens, morepreferably a C₁₋₃ alkyl optionally substituted by 1, 2 or 3 F or Cl),—SR¹¹ (preferably, R¹¹ is C₁₋₆ alkyl optionally substituted by 1, 2, 3or more halogens), more preferably C₁₋₃ alkyl optionally substituted by1, 2 or 3 F or Cl), or phenyl; and preferably, wherein the alkyl,alkylene, cyclic hydrocarbyl group, heterocyclic group, phenyl andheteroaryl are optionally further substituted by 1, 2, 3 or moresubstitutes independently selected from the group consisting of F, Cl,Br, I, OH, oxo, amino, cyano, nitro, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,C₅₋₆ cyclic hydrocarbyl group, 5- to 7-membered monocyclic heterocyclicgroup, phenyl, 5- to 6-membered heteroaryl; preferably F, Cl, OH, amino,cyano, nitro, C₁₋₄ alkyl and halogenated C₁₋₄ alkyl; or R¹³, eachoccurrence, is independently selected from the group consisting of—P(O)R¹¹R¹², wherein preferably, R¹¹ and R¹², at each occurrence, areeach independently a C₁₋₄ alkyl optionally substituted by 1, 2, 3 ormore halogens, preferably a C₁₋₄ alkyl optionally substituted by 1, 2 or3 F or Cl, more preferably methyl, ethyl, propyl or isopropyl, morepreferably methyl; and C₃₋₁₀ cyclic hydrocarbyl group or 3- to10-membered heterocyclic group, which is substituted by CM alkyl,preferably C₃₋₇ cyclic hydrocarbyl group or 4- to 7-memberedheterocyclic group, which is substituted by C₁₋₄ alkyl, preferably C₅₋₇cyclic hydrocarbyl group or 5- to 7-membered monocyclic heterocyclicgroup, which is substituted by C₁₋₄ alkyl, wherein the alkyl isoptionally substituted by 1, 2, 3 or more OH or halogens, preferablyoptionally substituted by 1, 2 or 3 OH, F or C1.
 9. (canceled)
 10. Thecompound according to claim 1, or a pharmaceutically acceptable salt,ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R is:

wherein R^(1a), R^(1b) together with X¹ to which they are attached forma group which is optionally substituted by 1, 2, 3 or more R¹³ and isselected from the group consisting of C₅₋₇ cyclic hydrocarbyl group; 5-to 10-membered heterocyclic group; C₆₋₁₀ aryl; and 5- to 10-memberedheteroaryl; and X⁴ is a direct bond.
 11. The compound according to claim10, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein the compound has a structure of formula(I-1) or formula (I′-1):


12. The compound according to claim 11, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R^(1a), R^(1b)together with X¹ to which they are attached form a group which isoptionally substituted by 1, 2, 3 or more R¹³ and is selected from thegroup consisting of C₅₋₇ cyclic hydrocarbyl group; 5-, 6- or 7-memberedmonocyclic heterocyclic group; and phenyl; or R^(1a), R^(1b) togetherwith X¹ to which they are attached form a group which is optionallysubstituted by 1, 2, 3 or more R¹³ and is selected from the groupconsisting of 5- to 10-membered heteroaryl (such as 5- to 6-memberedheteroaryl), preferably the heteroaryl being selected from the groupconsisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, isoindolyl,indazolyl, benzimidazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, pyrrolopyrimidinyl, pyrrolopyridyl,pyrazolopyrimidinyl, pyrazolopyridyl, imidazopyridyl, purinyl;preferably selected from the group consisting of pyrazolyl, pyrimidinyl,quinazolinyl and pyrazolopyrimidinyl; more preferably selected from thegroup consisting of

 and preferably, wherein R¹³ is a C₁₋₄ alkyl, C₆₋₁₀ aryl or —C₁₋₄alkylene-R¹¹, which is optionally substituted by 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, OH, amino,cyano, C₁₋₄ alkyl and phenyl; and wherein R¹¹ is selected from the groupconsisting of a C₅₋₇ cyclic hydrocarbyl group, 5- to 7-memberedmonocyclic heterocyclic group, phenyl and 5- to 6-membered heteroaryl;preferably, R¹³ is a C₁₋₄ alkyl, phenyl or —C₁₋₄-alkylene-phenyl, whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of F, Cl, Br, C₁₋₄ alkyl and phenyl;or R¹³ is a phenyl optionally substituted by 1.2 or 3 substituentsindependently selected from the group consisting of F, Cl, Br and C₁₋₄alkyl: preferably, R¹³ is a phenyl or fluorophenyl (preferably

 or R¹³ is a C₁₋₄ alkyl or —C₁₋₄-alkylene-phenyl, which is optionallysubstituted by 1, 2 or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl and phenyl: preferably, R¹³ is methyl or—CH₂-phenyl; or R^(1a), R^(1b) together with X¹ to which they areattached form a group selected from the group consisting of phenyl,


13. (canceled)
 14. (canceled)
 15. (canceled)
 16. (canceled) 17.(canceled)
 18. The compound according to claim 1, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein Ris:

wherein R^(1a) is a group which is optionally substituted by 1, 2, 3 ormore R¹³ and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cyclic hydrocarbyl group, 4- to 7-memberedmonocyclic heterocyclic group, 8- to 10-membered benzo-fusedheterocyclic group, phenyl, 5- to 10-membered heteroaryl, —C₁₋₃alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-memberedmonocyclic heterocyclic group), —C₁₋₃ alkylene-(8- to 10-memberedbenzo-fused heterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃alkylene-(5- to 10-membered heteroaryl); preferably, from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₅₋₇ cyclichydrocarbyl group, 4- to 7-membered monocyclic heterocyclic group(including 5-, 6- or 7-membered monocyclic heterocyclic group), 8- to10-membered benzo-fused heterocyclic group, phenyl, 5- to 10-memberedheteroaryl (including 5- to 6-membered heteroaryl), —C₁₋₃ alkylene-C₃₋₇cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-membered monocyclicheterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃ alkylene-(5- to6-membered heteroaryl); preferably, wherein R¹³ is selected from thegroup consisting of C₁₋₄ alkyl-O—; halogen (including F, Cl, Br and I);and C₁₋₄ alkyl or phenyl, which is optionally substituted by 1, 2 or 3substituents independently selected from halogen; and R^(1b) does notexist or is selected from the group consisting of H and R^(1a). 19.(canceled)
 20. The compound according to claim 18, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, whereinR^(1b) does not exist, and X¹ does not exist.
 21. The compound accordingto claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof wherein the compound has a structure of formula (I-2)or formula (I′-2):


22. The compound according to claim 20, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein X⁴ is selectedfrom the group consisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(r), preferably is C(═O),—O—C(═O)— or —NR¹⁰—C(═O)—.
 23. The compound according to claim 18, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1a) is a group selected from the group consisting ofoptionally substituted C₃₋₇ cyclic hydrocarbyl group, optionallysubstituted 4- to 7-membered monocyclic heterocyclic group, optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group, optionallysubstituted phenyl, optionally substituted 5- to 10-membered heteroaryl,-optionally substituted C₁₋₃ alkylene-(optionally substituted C₃₋₇cyclic hydrocarbyl group), -optionally substituted C₁₋₃alkylene-(optionally substituted 5- to 7-membered monocyclicheterocyclic group), -optionally substituted C₁₋₃ alkylene-(optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group),-optionally substituted C₁₋₃ alkylene-optionally substituted phenyl, and-optionally substituted C₁₋₃ alkylene-(optionally substituted 5- to10-membered heteroaryl); preferably, R^(1a) is a group selected from thegroup consisting of optionally substituted C₃₋₇ cyclic hydrocarbylgroup, optionally substituted 4- to 7-membered monocyclic heterocyclicgroup, optionally substituted 8- to 10-membered benzo-fused heterocyclicgroup, optionally substituted phenyl, optionally substituted 5- to10-membered heteroaryl, —C₁₋₃ alkylene-(optionally substituted C₃₋₇cyclic hydrocarbyl group), —C₁₋₃ alkylene-(optionally substituted 5- to7-membered monocyclic heterocyclic group), —C₁₋₃ alkylene-(optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group),-optionally substituted C₁₋₃ alkylene-optionally substituted phenyl, and—C₁₋₃ alkylene-(optionally substituted 5- to 10-membered heteroaryl);wherein the term “optionally substituted” means being substituted by 1,2, 3 or more R¹³; R^(1b) does not exist; X¹ does not exist; and X⁴ isselected from the group consisting of C(═O), S(═O)_(y), —OC(═O)— and—NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein R¹⁰ is preferably FI or C₁₋₆alkylene.
 24. The compound according to claim 23, or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, whereinR^(1a) is a group selected from the group consisting of an optionallysubstituted 5-, 6- or 7-membered monocyclic heterocyclic group, anoptionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl; preferably a group selected fromthe group consisting of an optionally substituted 5-, 6- or 7-memberedmonocyclic heterocyclic group, an optionally substituted phenyl, and—C₁₋₃ alkylene-optionally substituted phenyl; or R^(1a) is a groupselected from the group consisting of an optionally substituted C₃₋₇cyclic hydrocarbyl group, wherein the cyclic hydrocarbyl group is, forexample, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; anoptionally substituted 4- to 7-membered monocyclic heterocyclic group,wherein the heterocyclic group is, for example

an optionally substituted 8- to 10-membered benzo-fused heterocyclicgroup, wherein the heterocyclic group is, for example,

an optionally substituted phenyl: optionally substituted C₁₋₃alkylene-optionally substituted phenyl: an optionally substituted 5- to10-membered heteroaryl, and —C₁₋₃ alkylene-(optionally substituted 5- to10-membered heteroaryl), wherein the heteroaryl is, for example

and wherein the term “optionally substituted” means being substituted by1, 2, 3 or more R¹³; preferably, wherein R¹³ is selected from the groupconsisting of halogen, OH, —NR¹¹R¹², cyano and C₁₋₄ alkyl; and phenyl,5-, 6- or 7-membered monocyclic heterocyclic group and 5- to 6-memberedheteroaryl, which are optionally substituted by 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, OH,—NR¹¹R¹², cyano and C₁₋₄ alkyl, and wherein R¹¹ and R¹² are eachindependently selected from the group consisting of H and C₁₋₄ alkyl(preferably methyl); preferably, R¹³ is selected from the groupconsisting of F, Cl, Br, —N(CH₃)₂, and C₁₋₄ alkyl; and phenyl, 5- to7-membered monocyclic heterocyclic group (such as

and 5- to 6-membered heteroaryl (such as

which are optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of F, Cl, Br and C₁₋₄ alkyl; or morepreferably, R^(1a) is selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl,


25. (canceled)
 26. (canceled)
 27. (canceled)
 28. The compound accordingto claim 23, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein X⁴ is selected from the group consisting ofC(═O), S(═O)_(y) and —O—C(═O)—, and wherein y is preferably
 2. 29. Thecompound according to claim 23, or a pharmaceutically acceptable salt,ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R³ is COOH,

and R⁴ is H.
 30. The compound according to claim 20, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁴ is a direct bond.
 31. The compound according toclaim 30, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein R^(1a) is —C₁₋₃ alkylenephenyl, preferably—CH₂-phenyl.
 32. The compound according to claim 22, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein: R^(1a) is selected from the group consisting of C₂₋₆alkenyl (preferably vinyl, 1-propenyl or 2-propenyl) and C₂₋₆ alkynyl(preferably ethynyl, 1-propynyl or 2-propynyl), which are optionallysubstituted by 1, 2, 3 or more R¹³; preferably, wherein R¹³ is selectedfrom the group consisting of phenyl and 5- to 6-membered heteroaryl,which are optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of halogen OH, amino, cyano and C₁₋₄alkyl; preferably, R¹³ is a phenyl or pyridyl, which is optionallysubstituted by 1, 2 or 3 substituents independently selected from thegroup consisting of F, Cl and Br; and X⁴ is C(═O) or —O—C(═O)—; orpreferably, R^(1a) is selected from the group consisting of


33. (canceled)
 34. (canceled)
 35. The compound according to claim 1, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CR¹⁰ or N.
 36. The compound according to claim35, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein X⁴ is a direct bond.
 37. The compoundaccording to claim 35, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein X⁴ is selected from thegroup consisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—,—O—S(═O)_(y)—, —NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(y)—, preferably is C(═O),—O—C(═O)— or —NR¹⁰—C(═O)—.
 38. The compound according to claim 35, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(1b) is selected from the group consisting of H andR^(1a), and preferably, X¹ is CH.
 39. The compound according to claim36, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein: R^(1a) is selected from the groupconsisting of C₂₋₆ alkenyl (such as vinyl, 1-propenyl or 2-propenyl) andC₂₋₆ alkynyl (such as ethynyl, 1-propynyl or 2-propynyl) which areoptionally substituted by 1, 2, 3 or more R¹³; and/or R^(1b) is selectedfrom the group consisting of C₁₋₄ alkyl optionally substituted by 1, 2,3 or more R¹³; preferably, wherein R¹³ is selected from the groupconsisting of C₁₋₄ alkyl, phenyl and 5- to 6-membered heteroaryl, whichare optionally substituted by 1, 2 or 3 substituents independentlyselected from the group consisting of halogen OH, amino, cyano and C₁₋₄alkyl; preferably, R¹³ is a C₁₋₄ alkyl or phenyl, which is optionallysubstituted by 1.2 or 3 substituents independently selected from thegroup consisting of F, Cl and Br; more preferably, R¹³ is a C₁₋₄ alkyl(such as methyl, ethyl, propyl, isopropyl or tert-butyl); or a phenyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom the group consisting of F, Cl and Br; or R^(1a) is

and/or R^(1b) is methyl, ethyl, n-propyl or isopropyl.
 40. (canceled)41. (canceled)
 42. The compound according to claim 39, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CH or N, preferably CH.
 43. The compoundaccording to claim 37, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein: R^(1a) is a groupselected from the group consisting of an optionally substituted C₃₋₇cyclic hydrocarbyl group, an optionally substituted 4- to 7-memberedmonocyclic heterocyclic group, an optionally substituted 8- to10-membered benzo-fused heterocyclic group, an optionally substitutedphenyl, an optionally substituted 5- to 10-membered heteroaryl,-optionally substituted C₁₋₃ alkylene-(optionally substituted C₃₋₇cyclic hydrocarbyl group), -optionally substituted C₁₋₃alkylene-(optionally substituted 5- to 7-membered monocyclicheterocyclic group), -optionally substituted C₁₋₃ alkylene-(optionallysubstituted 8- to 10-membered benzo-fused heterocyclic group),-optionally substituted C₁₋₃ alkylene-optionally substituted phenyl, and-optionally substituted C₁₋₃ alkylene-(optionally substituted 5- to10-membered heteroaryl); preferably, R^(1a) is a group selected from thegroup consisting of an optionally substituted C₃₋₇ cyclic hydrocarbylgroup, an optionally substituted 4- to 7-membered monocyclicheterocyclic group, an optionally substituted 8- to 10-memberedbenzo-fused heterocyclic group, an optionally substituted phenyl, anoptionally substituted 5- to 10-membered heteroaryl, —C₁₋₃alkylene-(optionally substituted C₃₋₇ cyclic hydrocarbyl group), —C₁₋₃alkylene-(optionally substituted 5- to 7-membered monocyclicheterocyclic group), —C₁₋₃ alkylene-(optionally substituted 8- to10-membered benzo-fused heterocyclic group), —C₁₋₃ alkylene-optionallysubstituted phenyl, and —C₁₋₃ alkylene-(optionally substituted 5- to10-membered heteroaryl); or R^(1a) is a group selected from the groupconsisting of an optionally substituted phenyl; —C₁₋₃alkylene-(optionally substituted C₃₋₇ cyclic hydrocarbyl group), thecyclic hydrocarbyl group being, for example, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; —C₁₋₃ alkylene-(optionally substituted 8- to10-membered benzo-fused heterocyclic group), the heterocyclic groupbeing, for example,

—C₁₋₃ alkylene-optionally substituted phenyl; an optionally substituted5- to 10-membered heteroaryl and —C₁₋₃ alkylene-(optionally substituted5- to 10-membered heteroaryl the heteroaryl being, for example,

and wherein the term “optionally substituted” means being substituted by1, 2, 3 or more R¹³; preferably, wherein R¹³ is selected from the groupconsisting of halogen, —OR¹¹ (preferably, R¹¹ is C₁₋₆ alkyl optionallysubstituted by 1, 2, 3 or more halogens, more preferably C₁₋₃ alkyloptionally substituted by 1, 2 or 3 F or Cl), —NR¹¹R¹², cyano and C₃₋₇cyclic hydrocarbyl group; and C₁₋₄ alkyl, C₂₋₄ alkenyl and C₂₋₄ alkynylwhich are optionally substituted by 1, 2, 3 or more halogens, andwherein R¹¹ and R¹² are each independently selected from the groupconsisting of H and C₁₋₄ alkyl (preferably methyl); preferably, R¹³ isselected from the group consisting of F, Cl, Br, OH, —OC₁₋₄ alkyl,—N(C₁₋₄ alkyl)₂, cyano, C₃₋₇ cyclic hydrocarbyl group, C₂₋₄ alkenyl andC₁₋₄ alkynyl; and C₁₋₄alkyl optionally substituted by 1, 2, 3 or more F,Cl or Br; more preferably, R¹³ is selected from the group consisting ofF, Cl, Br, —OCH₃, —N(CH₃)₂, cyano, cyclopropyl, vinyl, 1-propenyl,2-propenyl, ethynyl, 1-propenyl, 2-propynyl, methyl, ethyl, n-propyl,isopropyl, tert-butyl and CF₃; or R¹³, at each occurrence, isindependently selected from the group consisting of —P(O)R¹¹R¹², whereinpreferably, R¹¹ and R¹², at each occurrence, are each independently aC₁₋₆ alkyl optionally substituted by 1, 2, 3 or more halogens,preferably a C₁₋₃ alkyl optionally substituted by 1, 2 or 3 F or Cl,more preferably methyl, ethyl, propyl or isopropyl, more preferablymethyl; and C₃₋₁₀ cyclic hydrocarbyl group or 3- to 10-memberedheterocyclic group, which is substituted by C₁₋₆ alkyl, preferably C₃₋₇cyclic hydrocarbyl group or 4- to 7-membered heterocyclic group, whichis substituted by C₁₋₆ alkyl, preferably C₅₋₇ cyclic hydrocarbyl groupor 5- to 7-membered monocyclic heterocyclic group, which is substitutedby C₁₋₃ alkyl, wherein the alkyl is optionally substituted by 1, 2, 3 ormore OH or halogens, preferably optionally substituted by 1, 2 or 3 OH,F or Cl; or R^(1a) is selected from the group consisting of


44. (canceled)
 45. (canceled)
 46. (canceled)
 47. The compound accordingto claim 43, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein R^(1b) is a group selected from the groupconsisting of H, an optionally substituted C₁₋₄ alkyl, an optionallysubstituted C₃₋₇ cyclic hydrocarbyl group, an optionally substitutedphenyl, -optionally substituted C₁₋₃ alkylene-(optionally substitutedC₃₋₇ cyclic hydrocarbyl group), and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl; preferably, R^(1b) is a groupselected from the group consisting of H, an optionally substituted C₁₋₄alkyl, an optionally substituted C₃₋₇ cyclic hydrocarbyl group, anoptionally substituted phenyl, —C₁₋₃ alkylene-optionally substitutedC₃₋₇ cyclic hydrocarbyl group), and —C₁₋₃ alkylene-optionallysubstituted phenyl; more preferably, R^(1b) is a group selected from thegroup consisting of H, phenyl; an optionally substituted C₁₋₄ alkyl, thealkyl being, for example, methyl, ethyl or isopropyl; an optionallysubstituted C₃₋₇ cyclic hydrocarbyl group and —C₁₋₃ alkylene-(C₃₋₇cyclic hydrocarbyl group), the cyclic hydrocarbyl group being, forexample, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and —C₁₋₃alkylene-phenyl; and wherein the term “optionally substituted” meansbeing substituted by 1, 2, 3 or more R¹³; wherein R¹³ is preferablyselected from the group consisting of halogen and C₁₋₄ alkyl, morepreferably selected from the group consisting of F, Cl, Br and methyl;or R^(1b) is selected from the group consisting of H, methyl, ethyl,isopropyl, CF₃CH₂, cyclopropyl,

phenyl,


48. (canceled)
 49. The compound according to claim 47, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CH or N, preferably N.
 50. The compound accordingto claim 43, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein X⁴ is selected from the group consisting ofC(═O) and S(═O)_(y), and wherein y is preferably
 2. 51. The compoundaccording to claim 43, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R³ is COOH or

and R⁴ is H.
 52. The compound according to claim 1, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein: R^(2a) is selected from the group consisting of anoptionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl; preferably, R^(2a) is selectedfrom the group consisting of an optionally substituted phenyl, and —C₁₋₃alkylene-optionally substituted phenyl; and/or R^(2b) is selected fromthe group consisting of an optionally substituted C₁₋₄ alkyl, anoptionally substituted phenyl, and -optionally substituted C₁₋₃alkylene-optionally substituted phenyl; preferably, R^(2b) is selectedfrom the group consisting of C₁₋₄ alkyl, an optionally substitutedphenyl, and —C₁₋₃ alkylene-optionally substituted phenyl; wherein theterm “optionally substituted” means being substituted by 1, 2, 3 or moreR¹³; preferably, wherein R¹³ is selected from the group consisting ofhalogen and —OR¹¹, and wherein R¹¹ is selected from C₁₋₄alkyl/preferably methyl); preferably, R¹³ is selected from the groupconsisting of F, Cl, Br and —OCH₃; or R^(2a) is selected from the groupconsisting of phenyl,

and/or R^(2b) is selected from the group consisting of methyl, phenyl,


53. (canceled)
 54. (canceled)
 55. The compound according to claim 43, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prod rugthereof, wherein the compound has a structure of formula (II) or formula(III):

wherein R^(1a), R^(1b), X¹, X⁴, R^(2a), R^(2b), X², R³, R⁴, h and k areas defined in claim
 43. 56. The compound according to claim 1, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R is:

wherein R^(1a) is a group which is optionally substituted by 1, 2, 3 ormore R¹³ and is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5-, 6- or7-membered monocyclic heterocyclic group, 8- to 10-membered benzo-fusedheterocyclic group, phenyl, 5- to 6-membered heteroaryl, —C₁₋₃alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to 7-memberedmonocyclic heterocyclic group), —C₁₋₃ alkylenephenyl and —C₁₋₃alkylene-(5- to 6-membered heteroaryl), preferably, wherein R¹³ isselected from the group consisting of C₁₋₄ alkyl-O—; halogen (includingF, Cl, Br and I); and C₁₋₄ alkyl or phenyl, which is optionallysubstituted by 1, 2 or 3 substituents independently selected fromhalogen; and R^(1b) and X¹ together form a bivalent C₅₋₇ cyclichydrocarbyl group or a bivalent 5-, 6- or 7-membered monocyclicheterocyclic group; or preferably, R^(1a) is phenyl; and R^(1b) and X¹together form

and X⁴ is selected from the group consisting of C(═O) and S(═O)_(y). 57.(canceled)
 58. (canceled)
 59. (canceled)
 60. The compound according toclaim 1, or a pharmaceutically acceptable salt, ester, stereoisomer,polymorph, solvate, N-oxide, isotopically labeled compound, metaboliteor prodrug thereof, wherein R is:


61. The compound according to claim 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein Y is a singlebond, NR¹⁰, O, S, methylene, ethylene, —CH₂—O—, —O—CH₂—, —CH₂—S—,—S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—, —CH═CH—, —CH═N— or —N═CH—.
 62. Thecompound according to any one of claims 1 to 9 and 61, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R is:

and the optionally substituted saturated or partially unsaturated fusedring system comprising 3 or more rings which is formed by R^(1a) andR^(1b) together with X¹ to which they are attached has a structure offormula (a):

wherein: ring A and ring B are each independently C₃₋₁₀ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl, or5- to 14-membered heteroaryl, preferably C₅₋₇ cyclic hydrocarbyl group(such as, cyclopentyl or cyclohexyl), 5- to 7-membered monocyclicheterocyclic group, phenyl, or 5- to 6-membered heteroaryl; “

” represents a single bond or a double bond; preferably, the fused ringsystem has a structure of formula (1) or formula (2):

wherein R^(5a) and R^(5b), at each occurrence, are each independentlyR¹⁰; R⁷ does not exist or is R¹⁰; and m and n, at each occurrence, areeach independently 0, 1, 2 or
 3. 63. The compound according to claim 62,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X¹ is CH or N.
 64. The compound according to claim 63,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein: the group of formula (1) has a structure selected fromthe group consisting of

or the group of formula (2) has a structure selected from the groupconsisting of


65. The compound according to claim 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R is:

and X⁶ is selected from the group consisting of O, S, NR¹⁰, —C(═O)—NR¹⁰—and —S(═O)_(y)—NR¹⁰—, preferably selected from the group consisting ofO, S, NH, N(C₁₋₆ alkyl), —C(═O)—NH—, —C(═O)—N(C₁₋₆ alkyl)-,—S(═O)_(y)—NH— and —S(═O)_(y)—N(C₁₋₆ alkyl)-, more preferably selectedfrom the group consisting of O, S, NH, N(C₁₋₄ alkyl) and —C(═O)—NH—,more preferably selected from the group consisting of O, S, NH, N(CH₃)and —C(═O)—NH—, more preferably selected from the group consisting of Oand S, even more preferably is O; and/or R⁹ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₅₋₇ cyclichydrocarbyl group, 5- to 7-membered monocyclic heterocyclic group,phenyl, 5- to 6-membered heteroaryl and phenyl-C₁₋₆ alkylene-,preferably selected from the group consisting of H, C₁₋₄ alkyl(including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl), C₂₋₄ alkenyl (including vinyl, 1-propenyl,2-propenyl, 2-butenyl and 3-butenyl), C₂₋₄ alkynyl (including ethynyl,1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl), phenyl and phenyl-C₁₋₄alkylene-(including phenyl-methylene- and phenyl-ethylene-), morepreferably is phenyl-C₁₋₄ alkylene-; the above alkyl, alkylene, alkenyl,alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl andheteroaryl are each optionally substituted by 1, 2, 3 or more R¹³; R¹³is as defined in claims 1 to 9; preferably, R¹³, at each occurrence, isindependently selected from the group consisting of halogen (includingF, Cl, Br, and I); OH; amino; cyano; nitro; and C₁₋₆ alkyl (includingC₁₋₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl and tert-butyl) and C₆₋₁₀ aryl (such as phenyl),which are optionally substituted by 1, 2, 3 or more substituentsindependently selected from the group consisting of halogen (includingF, Cl, Br, and I), OH, amino, cyano, nitro and phenyl.
 66. (canceled)67. The compound according to claim 65, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein R is selectedfrom the group consisting of


68. (canceled)
 69. The compound according to claim 65, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X³ is CH.
 70. The compound according to claim 1, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(2a), R^(2b) together with X² to which they areattached form a group which is optionally substituted by 1, 2, 3 or moreR¹³ and is selected from the group consisting of C₅₋₇ cyclic hydrocarbylgroup; 5-, 6- or 7-membered monocyclic heterocyclic group; phenyl; and5- to 6-membered heteroaryl, preferably, wherein R¹³ is C₁₋₄ alkyl orphenyl-C₁₋₄-alkyl-, which is optionally substituted by 1, 2 or 3substituents independently selected from the group consisting of C₁₋₄alkyl and phenyl; and X⁵ is a direct bond.
 71. (canceled)
 72. Thecompound according to claim 1, or a pharmaceutically acceptable salt,ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R^(2a) is a group whichis optionally substituted by 1, 2, 3 or more R¹³ and is selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₅₋₇cyclic hydrocarbyl group, 5-, 6- or 7-membered monocyclic heterocyclicgroup, 8- to 10-membered benzo-fused heterocyclic group, phenyl, 5- to6-membered heteroaryl, —C₁₋₃ alkylene-C₃₋₇ cyclic hydrocarbyl group,—C₁₋₃ alkylene-(5- to 7-membered monocyclic heterocyclic group), —C₁₋₃alkylenephenyl and —C₁₋₃ alkylene-(5- to 6-membered heteroaryl),preferably, wherein R¹³ is selected from the group consisting of C₁₋₄alkyl-O—; halogen (including F, Cl, Br, and I); and C₁₋₄ alkyl orphenyl, which is optionally substituted by 1, 2 or 3 substituentsindependently selected from halogen; and R^(2b) does not exist or isselected from the group consisting of H and R^(2a).
 73. The compoundaccording to claim 72, or a pharmaceutically acceptable salt, ester,stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R^(2b) does not exist,and X² does not exist.
 74. The compound according to claim 73, or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁵ is selected from the group consisting of C(═O),S(═O)_(y), —O—C(═O)—, —S—C(═O)—, —O—S(═O)_(y)—, —NR¹⁰—C(═O)— and—NR¹⁰—S(═O)_(r), preferably is C(═O), —O—C(═O)— or —NR¹⁰—C(═O)—.
 75. Thecompound according to claim 72, or a pharmaceutically acceptable salt,ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof, wherein R^(2a) is a groupselected from the group consisting of an optionally substituted 5-, 6-or 7-membered monocyclic heterocyclic group, an optionally substitutedphenyl, and -optionally substituted C₁₋₃ alkylene-optionally substitutedphenyl, wherein the term “optionally substituted” means beingsubstituted by 1, 2, 3 or more R¹³; R^(2b) does not exist; X² does notexist; and X⁵ is selected from the group consisting of C(═O), S(═O)_(y),—OC(═O)— and —NR¹⁰—C(═O)— and —NR¹⁰—S(═O)_(y)—, wherein R¹⁰ ispreferably H or C₁₋₆ alkylene.
 76. The compound according to claim 72,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X² is CR¹⁰ or N, and wherein R¹⁰ is preferably H, OH orC₁₋₄ alkyl (such as methyl).
 77. The compound according to claim 76, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X⁵ is a direct bond; or X⁵ is selected from the groupconsisting of C(═O), S(═O)_(y), —O—C(═O)—, —S—C(═O)—, —O—S(═O)_(y),—NR¹⁰—C(═O)— or —NR¹⁰—S(═O)_(y)—, preferably is C(═O), —O—C(═O)— or—NR¹⁰—C(═O)—.
 78. (canceled)
 79. The compound according to claim 76, ora pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(2b) is selected from the group consisting of H andR^(2a), and preferably, X² is CH.
 80. The compound according to claim 1,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R^(2a) is a group which is optionally substituted by 1,2, 3 or more R¹³ and is selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₅₋₇ cyclic hydrocarbyl group, 5-, 6-or 7-membered monocyclic heterocyclic group, 8- to 10-memberedbenzo-fused heterocyclic group, phenyl, 5- to 6-membered heteroaryl,—C₁₋₃ alkylene-C₃₋₇ cyclic hydrocarbyl group, —C₁₋₃ alkylene-(5- to7-membered monocyclic heterocyclic group), —C₁₋₃ alkylenephenyl and—C₁₋₃ alkylene-(5- to 6-membered heteroaryl), preferably, wherein R¹³ isselected from the group consisting of C₁₋₄ alkyl-O—; halogen (includingF, Cl, Br, and I); and C₁₋₄ alkyl or phenyl, which is optionallysubstituted by 1, 2 or 3 substituents independently selected fromhalogen: R^(2b) and X² together form a bivalent C₅₋₇ cyclic hydrocarbylgroup or a bivalent 5-, 6- or 7-membered monocyclic heterocyclic group;and X⁵ is selected from the group consisting of C(═O) and S(═O)_(y). 81.(canceled)
 82. (canceled)
 83. The compound according to claim 1, or thepharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein R′ is:


84. The compound according to claim 1, or the pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, wherein Zis a single bond, NR¹⁰, O, S, methylene, ethylene, —CH₂—O—, —O—CH₂—,—CH₂—S—, —S—CH₂—, —CH₂—NR¹⁰—, —NR¹⁰—CH₂—, —CH═CH—, —CH═N— or —N═CH—. 85.The compound according to claim 84, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the optionallysubstituted saturated or partially unsaturated fused ring systemcomprising 3 or more rings which is formed by R^(2a) and R^(2b) togetherwith X² to which they are attached has a structure of formula (b):

wherein: ring C and ring D are each independently C₃₋₁₀ cyclichydrocarbyl group, 3- to 10-membered heterocyclic group, C₆₋₁₀ aryl or5- to 14-membered heteroaryl, preferably C₅₋₇ cyclic hydrocarbyl group,5- to 7-membered monocyclic heterocyclic group, phenyl or 5- to6-membered heteroaryl; “

” represents a single bond or a double bond; preferably the fused ringsystem has a structure of formula (3) or formula (4):

wherein R^(6a) and R^(6b), at each occurrence, are each independentlyR¹⁰; R⁸ does not exist or is R¹⁰; and p and q, at each occurrence, areeach independently 0, 1, 2 or
 3. 86. The compound according to claim 85,or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, wherein X², at each occurrence, is independently CR¹⁰ or N, andwherein R¹⁰ is H, OH, amino or C₁₋₄ alkyl (such as methyl).
 87. Thecompound according to claim 86, or a pharmaceutically acceptable salt,ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeledcompound, metabolite or prodrug thereof wherein: the group of formula(3) has a structure selected from the group consisting of

or the group of formula (4) has a structure selected from the groupconsisting of


88. The compound according to claim 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein: the compoundhas a structure of formula (I-a) or formula (I′-a):

particularly, the structure of formula (IV) or formula (V):

the structure of formula (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7)or (a-8):

or the compound has a structure of formula (I-b) or formula (I′-b):

particularly, the structure of formula (b-1), (b-2), (b-3) or (b-4):


89. The compound according to claim 1, or a pharmaceutically acceptablesalt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopicallylabeled compound, metabolite or prodrug thereof, wherein the compoundhas a structure of No. Structure C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

C19

C20

C21

C22

C23

C24

C25

C26

C27

C28

C29

C30

C31

C32

C33

C34

C35

C36

C37

C38

C39

C40

C41

C42

C43

C44

C45

C46

C47

C48

C49

C50

C51

C52

C53

C54

C55

C56

C57

C58

C59

C60

C61

C62

C63

C64

C65

C66

C67

C68

C69

C70

C71

C72

C73

C74

C75

C76

C77

C78

C79

C80

C81

C82

C83

C84

C85

C86

C87

C88

C89

C90

C91

C92

C93

C94

C95

C96

C97

C98

C99

C100

C101

C102

C103

C104

C105

C106

C107

C108

C109

C110

C111

C112

C113

C114

C115

C116

C117

C118

C119

C120

C121

C122

C123

C124

C125

C126

C127

C128

C129

C130

C131

C132

C133

C134

C135

C136

C137

C138

C139

C140

C141

C142

C143

C144

C145

C146

C147

C148

C149

C150

C151

C152

C153

C154

C155

C156

C157

C158

C159

C160

C161

C162

C163

C164

C165

C166

C167

C168

C169

C170

C171

C172

C173

C174

C177

C178

C179

C180

C181

C182

C183

C184

C185

C186

C187

C188

C189

C190

C191

C192

C193

C194

C195

C196

C197

C198

C199

C200

C201

C202

C203

C204

C205

C206

C207

C208

C209

C210

C211

C212

C213

C214

C215

C216

C217

C218

C219

C220

C221

C222

C223

C224

C225

C226

C227

C228

C229

C230

C231

C232

C233

C234

C235

C236

C237

C238

C239

C240

C241

C242

C243

C244

C245

C246

C247

C248

C249

C250

C251

C252

C253

C254

C255

C256

C257

C258

C259

C260

C261

C262

C263

C264

C265

C266

C267

C268

C269

C270

C271

C272

C273

C274

C275

C276

C277

C278

C279

C280

C281

C282

C283

C284

C285

C286

C287

C288

C289

C290

C291

C292

C293

C294

C295

C296

C297

C298

C299

C300

C301

C302

C303

C304

C305

C306

C307

C308

C309

C310

C311

C312

C313

C314

C315

C316

C317

C318

C319


90. A pharmaceutical composition comprising a prophylactically ortherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, and a pharmaceutically acceptable carrier, and thepharmaceutical composition is preferably in the form of a solid,semi-solid, liquid, or gas preparation.
 91. Use of the compound of claim1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph,solvate, N-oxide, isotopically labeled compound, metabolite or prodrugthereof, or the pharmaceutical composition according to claim 90 in themanufacture of a medicament for regulating a reproductive functionassociated with AT₂ receptors (including menstrual cycle, fertility, andhormonal balances of the estrus cycle) in a female patient, or for theprophylaxis or the treatment of an AT₂ receptor-mediated disorder or asymptom associated therewith, preferably, the AT₂ receptor-mediateddisorder being selected from cerebrovascular disorders (includingcerebrovascular spasm and cerebral ischemia); cognitive disorders(including amnesia, senile dementia, AIDS related dementia and Down'ssyndrome); central nervous system diseases or disorders (includingaddiction such as alcoholism, anxiety-depression or dysthymic disorders,epilepsy, hyperactivity, pain, Parkinson's disease, psychosis, sleepdisorders, irregular autonomic function, and tardive dyskinesia,schizophrenia, demyelinating diseases such as multiple sclerosis andamyotrophic lateral sclerosis); respiratory diseases (includingbronchospasm, asthma, chronic obstructive airways disease), neuraltumors; inflammatory diseases (including inflammatory bowel disease andosteoarthritis); gastrointestinal (GI) diseases or disorders (includingulcerative colitis, Crohn's disease and incontinence); disorders ofblood flow caused by vasodilation; hypersensitivity disorders (includingallergies such as eczema, rhinitis and contact dermatitis); vasospasticdiseases (including angina, migraine and Reynaud's disease); fibrosingand collagen diseases (including scleroderma and eosinophilicfascioliasis); reflex sympathetic dystrophy (including shoulder/handsyndrome); stress related somatic disorders: peripheral neuropathy;neuralgia; autoimmune disease (including systemic lupus erythematosus,rheumatoid arthritis, psoriasis and graft versus host disease); andrheumatic diseases (including fibrositis); neuropathic conditions(including primary neuropathy and secondary neuropathy, such asperipheral neuropathy) or symptoms associated with the same (includinghyperesthesia-hyperalgesia, allodynia, spontaneous burning pain,numbness, weakness, burning pain, shooting pain, and loss of reflexes),preferably neuropathic pain; wherein the secondary neuropathy includesdiabetic neuropathy; Herpes Zoster-related neuropathy; uremia-associatedneuropathy; amyloidosis neuropathy; HIV sensory neuropathies; hereditarymotor and sensory neuropathies; hereditary sensory neuropathies;hereditary sensory and autonomic neuropathies; hereditary neuropathieswith ulcero-mutilation; nitrofurantoin neuropathy; tomaculousneuropathy; neuropathy caused by nutritional deficiency; neuropathycaused by kidney failure and complex regional pain syndrome; neuropathescaused by repetitive activities (such as typing or working on anassembly line); peripheral neuropathies caused by antiretroviral drugs(such as zalcitabine and didanosine), antibiotics (such metronidazoleand isoniazid), gold compounds, chemotherapy drugs (such asvincristine), alcohol, lead, arsenic, mercury and organophosphatepesticides; peripheral neuropathies associated with infectious processes(such as Guillian-Barre syndrome); a condition characterized by neuronalhypersensitivity, including a hyperalgesic condition, such asfibromyalgia and irritable bowel syndrome; a disorder associated withaberrant nerve regeneration, including neuronal hypersensitivity, breastpain, interstitial cystitis, vulvodynia, a cancer chemotherapy-inducedneuropathy; inflammatory pain that can be due to conditions that arecharacterized by inflammation (including burns such as chemical,frictional or thermal burns; autoimmune diseases such as rheumatoidarthritis; inflammatory bowel disease such as Crohn's disease andcolitis; osteoarthritis, carditis, dermatitis, myositis, neuritis andcollagen vascular diseases); impaired nerve conduction velocity whichmay be associated with a neuropathic condition as described above (suchas a peripheral neuropathy 1 as well as Carpel Tunnel Syndrome, ulnarneuropathy, Guillian-Barre Syndrome, fascioscapulohumeral musculardystrophy and spinal disc herneation; a cell proliferative disorder,including a cancer (including leukaemia, melanoma, prostate cancer,breast cancer, ovarian cancer, basal cell carcinoma, squamous cellcarcinoma, sarcoma-fibrosarcoma, colon cancer, lung cancer); and anon-cancerous proliferative disorder (including dermatological disorderssuch as warts, keloids, psoriasis, proud flesh disorder and also thereduction in scar tissue and cosmetic remodelling); and a disorderassociated with an imbalance between bone resorption and bone formation,including osteoporosis.
 92. (canceled)
 93. (canceled)
 94. (canceled) 95.A method for regulating a reproductive function associated with AT₂receptors (including menstrual cycle, fertility, and hormonal balancesof the estrus cycle) in a female patient, or for the prophylaxis or thetreatment of an AT₂ receptor-mediated disorder or a symptom associatedtherewith, comprising administering to a subject in need thereof aneffective amount of the compound of claim 1 or a pharmaceuticallyacceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide,isotopically labeled compound, metabolite or prodrug thereof, or thepharmaceutical composition according to claim 90, preferably, the AT₂receptor-mediated disorder being selected from cerebrovascular disorders(including cerebrovascular spasm and cerebral ischemia); cognitivedisorders (including amnesia, senile dementia, AIDS related dementia andDown's syndrome); central nervous system diseases or disorders(including addiction such as alcoholism, anxiety, depression ordysthymic disorders, epilepsy, hyperactivity, pain, Parkinson's disease,psychosis, sleep disorders, irregular autonomic function, and tardivedyskinesia, schizophrenia, demyelinating diseases such as multiplesclerosis and amyotrophic lateral sclerosis); respiratory diseases(including bronchospasm, asthma, chronic obstructive airways disease),neural tumors; inflammatory diseases (including inflammatory boweldisease and osteoarthritis); gastrointestinal (Gf) diseases or disorders(including ulcerative colitis, Crohn's disease and incontinence);disorders of blood flow caused by vasodilation; hypersensitivitydisorders (including allergies such as eczema, rhinitis and contactdermatitis); vasospastic diseases (including angina, migraine andReynaud's disease); fibrosing and collagen diseases (includingscleroderma and eosinophilic fascioliasis); reflex sympathetic dystrophy(including shoulder/hand syndrome); stress related somatic disorders:peripheral neuropathy: neuralgia: autoimmune disease (including systemiclupus erythematosus, rheumatoid arthritis, psoriasis and graft versushost disease); and rheumatic diseases (including fibrositis);neuropathic conditions (including primary neuropathy and secondaryneuropathy, such as peripheral neuropathy) or symptoms associated withthe same (including hyperesthesia-hyperalgesia, allodynia, spontaneousburning pain, numbness, weakness, burning pain, shooting pain, and lossof reflexes), preferably neuropathic pain; wherein the secondaryneuropathy includes diabetic neuropathy; Herpes Zoster-relatedneuropathy; uremia-associated neuropathy; amyloidosis neuropathy; HIVsensory neuropathies; hereditary motor and sensory neuropathies;hereditary sensory neuropathies; hereditary sensory and autonomicneuropathies; hereditary neuropathies with ulcero-mutilation;nitrofurantoin neuropathy; tomaculous neuropathy; neuropathy caused bynutritional deficiency; neuropathy caused by kidney failure and complexregional pain syndrome; neuropathes caused by repetitive activities(such as typing or working on an assembly line); peripheral neuropathiescaused by antiretroviral drugs (such as zalcitabine and didanosine),antibiotics (such metronidazole and isoniazid), gold compounds,chemotherapy drugs (such as vincristine), alcohol, lead, arsenic,mercury and organophosphate pesticides; peripheral neuropathiesassociated with infectious processes (such as Guillian-Barre syndrome);a condition characterized by neuronal hypersensitivity, including ahyperalgesic condition, such as fibromyalgia and irritable bowelsyndrome; a disorder associated with aberrant nerve regeneration,including neuronal hypersensitivity, breast pain, interstitial cystitis,vulvodynia, a cancer chemotherapy-induced neuropathy; inflammatory painthat can be due to conditions that are characterized by inflammation(including burns such as chemical, frictional or thermal burns;autoimmune diseases such as rheumatoid arthritis; inflammatory boweldisease such as Crohn's disease and colitis; osteoarthritis, carditis,dermatitis, myositis, neuritis and collagen vascular diseases); impairednerve conduction velocity which may be associated with a neuropathiccondition as described above (such as a peripheral neuropathy) as wellas Carpel Tunnel Syndrome, ulnar neuropathy, Guillian-Barre Syndrome,fascioscapulohumeral muscular dystrophy and spinal disc herneation; acell proliferative disorder, including a cancer (including leukaemia,melanoma, prostate cancer, breast cancer, ovarian cancer, basal cellcarcinoma, squamous cell carcinoma, sarcoma-fibrosarcoma, colon cancer,lung cancer); and a non-cancerous proliferative disorder (includingdermatological disorders such as warts, keloids, psoriasis, proud fleshdisorder and also the reduction in scar tissue and cosmeticremodelling); and a disorder associated with an imbalance between boneresorption and bone formation, including osteoporosis.